1977-1978	B.Sc. Hebrew University, Jerusalem, Biology
1980-1985	PhD. Hebrew University, Jerusalem, Genetics

Thesis subject: "Role of DNA-repair genes in meiosis of the yeast Saccharomyces cerevisiae."

Employment

2003-present	Full Professor, Department of Molecular Microbiology and Biotechnology, Tel Aviv University.
2002-2004	Chairman, Department of Molecular Microbiology and Biotechnology, Tel Aviv University.
2000-2001	Visiting Scientist, Whitehead Institute, M.I.T., Cambridge, MA, USA
1998-2003	Associate Professor, Department of Molecular Microbiology and Biotechnology, Tel Aviv University.
1994-1995	Visiting Scientist, Department of Genetics, University of Washington, Seattle, WA, USA.
1992-1998	Senior lecturer, Department of Molecular Microbiology and Biotechnology, Tel Aviv University.
1988-1992	Lecturer, Department of Molecular Microbiology and Biotechnology, Tel Aviv University.
1985-1988	Research associate, Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL., USA. Area: Homologous recombination in yeast

Other Appointments and Awards

1988	The Alon Fellowship Prize
1994-1995	Visiting Scientist, Department of Genetics, University of Washington, Seattle, WA, USA
1999	The Prof. Nathan Treinin Prize, by the Israel Cancer Association
1999-present	Editor, Current Genetics.
2000-2001	Visiting Scientist, Whitehead Institute, M.I.T., Cambridge, MA, USA.
2003-present	Editor, FEMS Microbiology Reviews.
2006-present	Board of Directors, The Genetic Society of Israel.
2008-present	The Pasha Gol Chair for Applied Microbiology

The Kupiec laboratory uses “the awesome power of yeast genetics” to investigate basic universal processes that are very hard to study in other organisms. Our basic methodology involves Molecular Biology techniques. As yeast is today the best understood eukaryotic organism, with more than half of its genes with a known function/activity, the new genetic and molecular tools developed in yeast have jump-started a REVOLUTION IN BIOLOGY: Systems Biology. We are able, for the first time, to ask very basic questions about the way genomes are organized, genes interact, proteins talk to each other, etc. This genome-wide approach requires novel tools, which we are helping to develop in cooperation with people from Computer Science at TAU. Most of the essential pathways, complexes and genes involved in basic cellular processes are conserved in evolution, and human orthologs are present for most of the genes we study.


Here are some of the basic biological questions that we are trying to understand, using the baker’s yeast (Saccharomyces cerevisiae) and fission yeast (Schizosaccharomyces pombe) as a model organisms:

1) DNA repair:
Our cells are constantly exposed to radiation and chemicals that cause damage to the DNA or even break the chromosomes in pieces. Even natural cellular metabolism creates oxidative stress and DNA damage. Luckily we have efficient mechanisms to repair the damage. Some of the questions we ask are:

• What do you do when you break one of your chromosomes? Is it possible to heal it? (Hint: yes). How is it done? Who does it? How are these processes regulated?
• Checkpoints: How do cell coordinate different events? Do cells really stop in the cell cycle “until DNA is repaired” and then continue? (Hint: no).
• Molecular biology of genes involved in DNA repair and cell cycle in yeast.
• Dissection of the mechanism of homologous recombination: Does recombination occur between homologous sequences at different genomic locations? (Hint: yes.). Then, how do you recognize a homologous sequence in the genome? Is there a molecular mechanism that “reads” the genome?

2) Stability of the eukaryotic genome:
Normal cells have remarkably stable karyotypes. You can easily identify to what species a cell belongs, just by looking at its chromosomes. However, cancer cells lose this stability, and start accumulating translocations, deletions, amplifications, etc. Many of the endpoints of these rearrangements fall in repeated sequences (sometimes called “junk DNA”) that fill-up our genomes. What prevents a high level of chromosomal aberrations as a consequence of recombination between repeated sequences?

Using a screen for mutants with high levels of recombination between repeats, we identified ELG1 (enhanced Levels of Genomic instability). Mutants in this gene hyper-recombine, lose chromosomes, have elongated telomeres, hyper-silencing in heterochromatic regions, etc. The Elg1 protein looks very similar to the large subunit of Replication Factor C (RFC), the clamp-loader in charge of loading PCNA onto DNA. PCNA is a clamp: a ring that circles DNA and holds polymerases in place so that their processivity is enhanced. RFC opens PCNA, so that it can encircle DNA, and then closes PCNA, at the expense of ATP. RFC is composed of a large subunit Rfc1 and 4 small subunits Rfc2-5. We have found 3 additional clamp loaders. All share the 4 small subunits, but in each case a different “brain protein” replaces Rfc1: Elg1, Ctf18 and Rad24. While Rad24 was found to load a PCNA-like clamp called 9-1-1 involved in damage sensing and checkpoint response initiation, Elg1 and Ctf18 have still uncharacterized functions. Here are some of the questions we are investigating about Elg1:

What is the function of Elg1? Does it load (or unload) PCNA or another clamp? When is it needed? When are the other complexes needed? Why does Elg1 interact with Ubiquitin and SUMO-processing enzymes? What are its connections to the other clamp loaders and to different repair mechanisms? What are its connections to chromatin deposition and silencing? What are its connections to DNA replication? What are its connections to telomere maintenance? Is the human ortholog involved in cancer?

3) Telomeres:
Telomeres are nucleoprotein complexes at the end of the eukaryotic chromosomes. In nearly all eukaryotes examined, the telomeric DNA consists of tracts of tandemly repeated sequences whose overall length is highly regulated. Telomeres are essential for chromosomal stability and integrity, as they prevent chromosome ends from being recognized as double strand breaks. Telomeric DNA is synthesized by the enzyme telomerase, which copies a short template sequence within its own RNA moiety. Telomerase is expressed at the early stages of development, but not in somatic cells. Conventional DNA polymerases are unable to replicate the very ends of chromosomes due to their primer dependency. As a result, telomeres of all differentiated somatic cells and tissues shorten with replicative age in vitro and donor age. Erosion of telomeric sequences eventually leads to the disappearance of the protective structure that caps telomeres, resulting in cells entering a non replicative state called senescence. Reactivation of telomerase in cultured cells results in extended life span leading to their immortalization. Thus, telomere shortening acts as a tumor suppressive mechanism. Moreover, it has been shown that replenishing telomeres by an activated telomerase is one of the few essential steps that a normal human fibroblast cell must take on its route to become malignant. Thus, understanding how telomere length is monitored has significant medical implications especially in the fields of aging and cancer.

In cells in which telomerase is expressed, telomeres do not grow increasingly longer and longer. An intricate regulation maintains the final telomere size. Some genes facilitate telomerase activity, whereas other restrict its activity and even degrade the telomeric DNA. We would like to understand what are the mechanisms that control telomeric length in yeast. A systematic screen, using a collection of 4,700 non-essential mutants, resulted in the identification of 170 genes that affect telomere length. Mutations in ~120 of them cause telomere shortening, whereas mutations in the other 50 cause telomere elongation. This large collection contains genes of a variety of activity and cellular location.
We would like to know how do all these genes work together to regulate telomere length. Are there pathways? Complexes? What are the interactions between the various elements? To answer these questions we are using a combination of Molecular Biology, Systems Biology, Genetics and Biochemistry. Bioinformatic models are used as a basis to plan possible experiments. The results are then incorporated into the model, to generate more predictions in a continuous cycle that progressively refines the model.

4) The TOR protein kinase:
The TOR protein kinases exhibit a conserved role in regulating cellular growth and proliferation. In mammals, mTOR is negatively regulated by the TSC1–TSC2 heterodimer. Mutations in either TSC1 or TSC2 cause a human syndrome, known as tuberous sclerosis complex (TSC), which is characterized by benign tumors and severe neurological defects. TSC2 encodes a GTPase-activating protein (GAP)
and together with TSC1 converts the small GTPase Rheb into its GDP-bound inactive form. Rheb binds mTOR and positively regulates its activity. In the fission yeast two TOR homologs are present. tor1 is required for starvation and stress responses, while tor2 is essential. Tor2 depleted cells show a phenotype very similar to that of wild-type cells starved for nitrogen, including arrest at the G1 phase of the cell cycle, induction of nitrogen-starvation-specific genes, and entrance into the sexual development pathway. The phenotype of tor2 mutants is in a striking contrast to the failure of tor1 mutants to initiate sexual development or arrest in G1 under nitrogen starvation conditions. Like in higher eukaryotes, the Tsc1-2 complex negatively regulates Tor2 in fission yeast. In contrast, the Tsc1-2 complex and Tor1 appear to work in parallel, both positively regulating amino acid uptake through the control of expression of amino acid permeases. Additionally, either Tsc1/2 or Tor1 are required for growth on a poor nitrogen source such as proline. Mutants lacking Tsc1 or Tsc2 are highly sensitive to the drug rapamycin under poor nitrogen conditions, suggesting that the function of Tor1 under such conditions is sensitive to rapamycin.

We would like to answer some of the following questions: What is the function of each of the Tor proteins? What is the nature of their interactions? How are they regulated? Why are mammalian cells and budding yeast so affected by rapamycin (an anticancer drug in clinical trials), whereas fission yeast can grow in its presence? How do the Tor proteins integrate signals from the environment to know when to grow? And how do they talk to the cell cycle machinery to coordinate growth (in volume) with cell division?

5) Mapping complex genetic traits:
The majority of the phenotypes in nature, including morphological, physiological and behavioral traits are affected by both genetic and environmental factors. Those traits, which are known as complex traits, exhibit measurable phenotypes with a characteristic normal distribution. Complex traits are characterized by a intricate pattern of heredity due to the influence of several genes and of the complex, nonlinear interactions among them. Dissecting the genetic component of the phenotypic diversity accrued by complex traits is one of the major challenges facing modern biology. Polygenic traits include economically and medically important determinants including agricultural crop yields and propensity to diseases such as heart attack, cancer and schizophrenia in humans.
The primary difficulty in identifying QTLs is that any single QTL explains only a small fraction of the phenotypic variation and thus the phenotype-genotype correlation is low. This has hampered progress in the mapping and identification of QTLs in any organism. Traditional approaches, which work so well in the context of Mendelian traits, met only limited success when applied to polygenic traits, which are characterized by small contributions to the phenotype by each individual gene.
The ability of yeast cells to grow at extreme extracellular pH is a quantitative measurable trait. Here, we use this trait in order to develop a novel strategy for characterizing complex traits and for QTLs mapping. Our strategy takes into consideration the difficulties explained above and is based on whole-genomic scale methods. The central principle is to analyze genetic networks rather than individual genes. A genetic network is defined as all the genes, and the interactions among them, which contribute to the expression of a phenotype. To map all QTLs composing the network we use a combination of several different methods to isolate the QTLs network and to incorporate it into a known background. We then use hybridization to DNA microarray chips to identify the individual genes. Using this method for the abilkity to grow at high pH has identified 13 genomic regions containing putative QTLs. We are in the process of identifying the underlying genes.

Thus, for the first time, we will be able to isolate the complete network of genes affecting a polygenic trait. Evolution acts at the level of the phenotype. How do these genes interact in order to create the final phenotype? Obviously, simple additive models in which each QTL adds a small contribution are too simplistic. We would like to quantitate the relative effect of each gene, and its interactions with the others. But WHO are these genes that can explain natural variation? Are they all related to the phenotype studied, or are they general modifiers of other genes?

6) Systems Biology:
New tools in Molecular Genetics allow us today to ask general questions on the way cells work. These are some examples of recent studies we have carried out in the lab:

6a: A BLAST for DNA microarrays: (with Ron Shamir)
The number of genome-wide experiments (DNA microarrays, protein-protein interaction studies, synthetic genetic interactions, etc) is increasing exponentially. The way researchers analyze their data today is by just looking at their own results. We would like to build a tool, akin to BLAST for DNA sequence analysis: you will be able to compare your results to all the other genome-wide experiments that were ever carried out. If you see that a group of genes behaves in your experiment similarly to the way they did in a few other, you obtain information both about your experimental setup (e.g., the drug you added) and the genes. A web interface (SIMBA) is being developed.

6b: Analysis of genetic interactions: (with Eytan Ruppin)
If you have a mutant that affects fitness, let’s say its fitness is 80% of wt (0.8), and another mutant has a fitness of 0.9. If you create double mutants, would you expect a fitness of 0.72? Why? What is the experimental evidence? Using genome-wide data we can start analyzing genetic interactions in a quantitative fashion, and create new models that may better explain the complexity of nature…

6c: Analysis of protein complexes: (with Eytan Ruppin and Roded Sharan)
Are protein complexes evolutionarily conserved? Do they lose or gain subunits? Do they lose or gain functions during evolution? A comparison of protein-protein interaction networks may give us some answers.

6d: Analysis of Chromatin factors: (With Ron Shamir)
Chromatin structure plays an important role in transcription regulation. While many factors that influence chromatin structure have been identified, the transcriptional programs in which they participate are still poorly understood. Chromatin modifiers participate in transcriptional control together with DNA-bound transcription factors. High-throughput experimental methods allow the genome-wide identification of binding sites for transcription factors as well as quantification of gene expression under various environmental and genetic conditions. We have developed a new methodology that uses the vast amount of available data to identify and characterize TFs that depend on specific CMs to carry out their transcriptional programs. We apply our methodology to S. cerevisiae, using a compendium of 170 gene expression profiles of strains defective for chromatin modifiers, taken from 26 different studies. Our method succeeds in identifying known intricate genetic interactions between chromatin modifiers and transcription factors and uncovers many previously unknown genetic interactions, giving the first genome-wide picture of the contribution of chromatin structure to transcription in a eukaryote.

OTHER SUBJECTS:

Other subjects in the lab:
• The Ty retro-transposon of yeast. Mechanisms of reverse-transcription, transposition and recombination.
• The link between cell cycle progression and pre-mRNA splicing. How come there are genes that control both processes? (example: The CDC40 gene).

1. Kupiec, M. and G. Simchen.(1984) Cloning and mapping of the RAD50 gene of Saccharomyces cerevisiae. Mol. Gen. Genet. 193: 525-531.

2. Kupiec, M. and G. Simchen. (1984) Cloning and integrative deletion of the RAD6 gene of Saccharomyces cerevisiae. Curr. Genet. 8: 559-556.

3. Kassir, Y., M. Kupiec, A. Shalom, and G. Simchen. (1985) Cloning and mapping of CDC40, a Saccharomyces cerevisiae gene with a role in DNA repair. Curr. Genet. 9: 253-257.

4. Kupiec, M., and G. Simchen. (1985) Arrest of the mitotic cell cycle and of meiosis in Saccharomyces cerevisiae by MMS. Molec. Gen. Genet. 201: 558-564.

5. Kupiec, M., and G. Simchen. (1986) DNA repair characterization of cdc40-1, a cell cycle mutant of Saccharomyces cerevisiae. Mutat. Res. 162: 33-40.

6. Kupiec, M., and G. Simchen. (1986) Regulation of the RAD6 gene of Saccharomyces cerevisiae in the mitotic cell cycle and in meiosis. Molec. Gen. Genet. 203: 538-543.

7. Kupiec, M. (1986) The RAD50 gene of Saccharomyces cerevisiae is not essential for vegetative growth. Curr. Genet. 10: 487-489.

8. Kupiec, M., and T. Petes. (1988a) Meiotic recombination between repeated transposable elements in Saccharomyces cerevisiae. Mol. Cell. Biol. 8: 2942-2954.

9. Kupiec, M., and T. Petes. (1988b) Allelic and ectopic recombination between Ty elements in yeast. Genetics 119: 549-559.

10. Petes, T., P. Detloff, S. Jinks-Robertson, S. Judd, M. Kupiec, D. Nag, A. Stapleton, L. Symington, A. Vincent, M. White. (1990) Recombination in yeast and the recombinant DNA technology. Genome 31: 536-540.

11. Melamed, C., Y. Nevo, and M. Kupiec. (1992) Involvement of cDNA in homologous recombination between Ty elements in Saccharomyces cerevisiae. Mol. Cell. Biol. 12:1613-1620.

12. Melamed, C., and M. Kupiec. (1992) Effect of donor copy number on the rate of gene conversion in the yeast Saccharomyces cerevisiae. Mol. Gen. Genet 235: 97-103.

13. Parket, A., and M. Kupiec. (1992) Ectopic recombination between Ty elements in Saccharomyces cerevisiae is not induced by DNA damage. Mol. Cell. Biol. 12: 4441-4448.

14. Roitgrund, C., R. Steinlauf, and M. Kupiec. (1993). Donation: A new, facile method of gene replacement in yeast. Mol. Gen. Genet. 237: 306-310.

15. Roitgrund, C., R. Steinlauf, and M. Kupiec. (1993). Donation of information to the unbroken chromosome during double strand break repair. Curr. Genet. 23: 414-422.

16. Silberman, R., and M. Kupiec. (1994). Plasmid-mediated induction of recombination in yeast. Genetics 137: 41-48.

17. Nevo-Caspi, Y., and M. Kupiec. (1994). Transcriptional induction of Ty recombination in yeast. Proc. Natl. Acad. Sci. USA 91: 12711-12715.

18. Parket, A., O. Inbar, and M. Kupiec. (1995). Recombination of Ty elements in yeast can be induced by a double-strand break. Genetics 140: 67-77.

19. Vaisman, N., A. Tzoulade, K. Robzyk, S. Ben-Yehuda, M. Kupiec, and Y. Kassir. (1995). The role of S. cerevisiae Cdc40p in DNA replication and mitotic spindle function. Mol. Gen. Genet. 247: 123-136.

20. Liefshitz, B., A. Parket, R. Maya, and M. Kupiec. (1995). The role of DNA repair genes in recombination between repeated genes in yeast. Genetics 140:1199-1211.

21. Nevo-Caspi, Y., and M. Kupiec. (1996). Induction of Ty recombination in yeast by cDNA and transcription: the role of the RAD1 and RAD52 genes. Genetics 144: 947-955.

22. Kupiec, M., Byers, B., Esposito, R.E., and A. P. Mitchell (1997). Meiosis and sporulation in Saccharomyces cerevisiae. In: The Molecular Biology of the Yeast Saccharomyces. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp. 889-1036.

23. Kupiec, M., and R. Steinlauf. (1997) Damage-induced ectopic recombination in the yeast Saccharomyces cerevisiae. Mutat. Res. 384: 33-44.

24. Nevo-Caspi, Y., and M. Kupiec. (1997) cDNA-mediated Ty recombination can take place in the absence of plus-strand cDNA synthesis, but not in the absence of the integrase protein. Current Genetics 32: 32-40.

25. Liefshitz, B., Steinlauf, R., Friedl, A., Eckardt-Schupp, F. and M. Kupiec (1998) Genetic interactions between mutants of the "error-prone" repair group of Saccharomyces cerevisiae and their effect on recombination and mutagenesis. Mutat. Res.407: 135-145.

26. Boger-Nadjar, E., N. Vaisman, S. Ben-Yehuda, Y. Kassir, and M. Kupiec (1998) Efficient initiation of S-phase in yeast requires Cdc40p, a protein involved in pre-mRNA splicing. Mol. Gen. Genet. 260: 232-241.

27. Ben Yehuda, S., I. Dix, C.S. Russell, S. Levy, J.D. Beggs and M. Kupiec (1998) Identification and functional analysis of hPRP17, the human homologue of the PRP17/CDC40 yeast gene involved in splicing and cell cycle control. RNA 4: 1304-1312.

28. Dix, I., Russell, C., Ben Yehuda, S., Kupiec, M., and J. D. Beggs (1999). The identification and characterisation of a novel splicing protein, Isy1p, of Saccharomyces cerevisiae. RNA 5: 360-368.

29. Cohen-Kupiec, R., Kupiec M., Sandbeck, K., and J.A. Leigh (1999) Functional conservation between the argininiosuccinate lyase of the archaeon Methanococcus maripaludis and the corresponding bacterial and eukaryal genes. FEMS Microbiol. Letters 173: 231-238.

30. Jablonovich, Z., B. Liefshitz, R. Steinlauf, and M. Kupiec (1999) Characterization of the role played by the RAD59 gene of Saccharomyces cerevisiae in ectopic recombination. Curr. Genet. 36: 13-20.

31. Inbar, O. and M. Kupiec (1999) Homology search and choice of homologous partner during mitotic recombination. Mol. Cell. Biol. 19: 4134-4142.

32. Ben-Yehuda, S., Russell, C.S., Dix, I., Beggs, J.D. and M. Kupiec (2000) Extensive genetic interactions between PRP8 and PRP17/CDC40, two yeast genes involved in pre-mRNA splicing and cell cycle progression. Genetics 154: 61-71.

33. Kupiec, M. (2000) Damage-induced recombination in the yeast Saccharomyces cerevisiae. Mutat. Res. 451: 91-105.

34. Ben-Yehuda, S., I. Dix, C.S. Russell, J.D. Beggs, and M. Kupiec (2000) Genetic and physical interactions between factors involved in both cell cycle progression and pre-mRNA splicing in Saccharomyces cerevisiae. Genetics 156: 1503-1517.

35. Russell, C. S., Ben-Yehuda¨S., Dix, I., Kupiec, M. and J. D. Beggs (2000) Functional analyses of interacting factors involved in both pre-mRNA splicing and cell cycle progression in Saccharomyces cerevisiae. RNA 6: 1565-1572.

36. Inbar, O., B. Liefshitz., G. Bitan and M. Kupiec (2000) The relationship between homology length and crossing-over during the repair of a broken chromosome. J. Biol. Chem. 275: 30833-30838.

37. Inbar, O. and M. Kupiec (2000) Recombination between divergent sequences leads to cell death in a mismatch-repair independent manner. Curr. Genet. 38: 23-32.

38. Friedl AA, Liefshitz B, Steinlauf R, and M. Kupiec (2001) Deletion of the SRS2 gene suppresses elevated recombination and DNA damage sensitivity in rad5 and rad18 mutants of Saccharomyces cerevisiae. Mutat Res. 486:137- 146.

39. Dahan, O. and M. Kupiec (2002) Mutations in genes of Saccharomyces cerevisiae encoding pre-mRNA splicing factors cause cell cycle arrest through activation of the spindle checkpoint. Nucleic Acid Res 30: 4361-4370.

40. Koren, A., Ben-Aroya, S. and M. Kupiec (2002) The control of meiotic recombination initiation: a role for the environment? Current Genetics 42: 129- 139.

41. Aylon, Y., Liefshitz, B., Bitan-Banin G. and M. Kupiec. (2003) Molecular dissection of mitotic recombination in the yeast Saccharomyces cerevisiae. Mol. Cell. Biol 23: 1403- 1417.

42. Koren, A., Ben-Aroya, S., Steinlauf R. and M. Kupiec (2003) Pitfalls of the synthetic lethality screen in Saccharomyces cerevisiae: an improved design. Current Genetics, in press.

43. Wheeler RT, Kupiec M, Magnelli P, Abeijon C, and G.R. Fink GR (2003) A Saccharomyces cerevisiae mutant with increased virulence. Proc Natl Acad Sci U S A 100: 2766-2770.

44. Ben-Aroya, S. Koren, A., Liefshitz, B., Steinlauf, R. and M. Kupiec (2003) ELG1, a novel yeast gene required for genome stability, forms a complex related to Replication actor C. Proc. Natl. Acad. Sci. USA 100: 9906-9911.

45. Aylon, Y. and M. Kupiec (2003) The checkpoint protein Rad24p of Saccharomyces cerevisiae is involved in processing double-strand break ends, recombination partner choice and recovery. Mol. Cell. Biol. 23: 6585-6596.

46. Tanay A., Sharan, R., Kupiec, M. and R. Shamir (2004) Integration and analysis of highly heterogeneous genome-wide data. Proc. Natl. Acad. Sci. USA 101: 2975-2980.

47. Ben-Aroya, S. Mieczkowski, P.A., Petes T.D. and M. Kupiec (2004) Interactions between a recombinational hotspot and a coldspot in Saccharomyces cerevisiae. Mol. Cell. 15: 221-231.

48. Dahan, O. and M. Kupiec (2004) The Saccharomyces cerevisiae gene CDC40/PRP17 controls cell cycle progression through differential splicing of ANC1. Nucl. Acid Res. 32: 2529-2540.

49. Gray, M., M. Kupiec, and S.M. Honigberg (2004) Site-specific genomic (SSG) and random domain-localized (RDL) mutagenesis in yeast. BioMedCentral Biotechnology 4: 7-12.

50. Askree, S.H., T. Yehuda,, S. Smolikov, R. Gurevich, J. Hawk, C. Cooker, A. Krauskopf, M. Kupiec and M.J. McEachern (2004) A genome-wide screen for Saccharomyces cerevisiae deletion mutants that affect telomere length. Proc. Natl. Acad. Sci. USA, 101: 8658-8663.

51. Aylon, Y., Liefshitz. B. and M. Kupiec (2004) The CDK regulates repair of double-strand breaks by recombination during the cell cycle. EMBO J. 23: 4868-4875.

52. Kaufman A, Kupiec M, and E. Ruppin (2004) Multi-Knockout Genetic Network Analysis: The Rad6 Example. Proc IEEE Comput Syst Bioinform Conf. 3: 332-340. PMID: 16448026.

53. Rog, O., Smolikov, S., Krauskopf A., and M. Kupiec (2005) The yeast VPS genes affect telomere length regulation. Curr. Genet. 47: 18-28.

54. Weisman, R., Roitburg I, Nahari T., and M. Kupiec (2005) Regulation of leucine uptake by tor1+ in fission yeast is sensitive to rapamycin. Genetics 169: 539-550.

55. Aylon, Y. and M. Kupiec (2005) Cell cycle dependent regulation of double strand break repair: a role for the CDK. Cell Cycle 4: 259-261.

56. Tanay, A., Steinfeld, I., Kupiec, M. and R. Shamir (2005) Integrative analysis of genome-wide experiments in the context of a large high-throughput data compendium. Mol. Syst. Biol. 1:2005.0002. Epub 2005 Mar 29.

57. Kaufman A, Keinan A, Meilijson I, Kupiec M. and E. Ruppin (2005) Quantitative analysis of genetic and neuronal multi-perturbation experiments. PLoS Comput Biol. 1(6): e64.

58. Havilio, M., Levanon , E.Y., Lerman, G., M. Kupiec and E. Eisenberg (2005) Evidence for abundant transcription of non-coding regions in the Saccharomyces cerevisiae genome. BMC Genomics 6: 93.

59. Deutscher, D Meilijson, I, Kupiec M. and E. Ruppin (2006) Multiple Knockout Analysis of Genetic Robustness in the Yeast Metabolic Network. Nature Genetics 38: 993-998.

60. Weisman R., Roitburg I., Schonbrun M., Harari R. and M. Kupiec (2006) Opposite effects of Tor1 and Tor2 on nitrogen starvation responses in fission yeast. Genetics 175: 1-10.

61. Kaplan, Yossi, and M. Kupiec (2006) A role for the yeast cell cycle/splicing factor Cdc40 in the G1/S transition. Current Genetics 51: 123-140.

62. Steinfeld, I., Shamir R. and M. Kupiec (2007) A genome-wide analysis in Saccharomyces cerevisiae demonstrates the influence of chromatin modifiers on transcription. Nature Genetics 39: 303-309.

63. Kupiec, M., Sharan R. and E. Ruppin (2007) Genetic interactions in yeast: Is Robustness Going Bust? [Invited News and Views for: Ihmels, J., Collins S.R., Schuldiner M., Krogan N.J., Weissman J.S. Genetic interactions reveal the true cost of gene loss for singleton and duplicate genes. Molecular Systems Biology 3:86 (2007)] Molecular Systems Biology, 3:97.

64. Haviv-Chesner, A., Kobayashi Y., Gabriel A. and M. Kupiec (2007) Capture of linear fragments at a double-strand break in yeast. Nucleic Acid Research 35: 5192-5202.

65. Tuller T, M. Kupiec and E. Ruppin (2007) Determinants of protein abundance and translation efficiency in Saccharomyces cerevisiae. PLoS Comput Biol 3(12): e248 doi:10.1371/journal.pcbi.0030248.

66. Shachar R., L. Ungar , M. Kupiec*, E. Ruppin* and R. Sharan* (2008) A Systems-level Approach to Mapping the Telomere-length Maintenance Gene Circuitry. Molec. Systems Biology 4: 172, doi:10.1038/msb.2008.13. * These authors contributed equally.

67. Barzel A. and M. Kupiec (2008) Finding a match: how do homologous sequences get together for recombination? Nat Rev Genet. 2008 Jan;9(1):27-37.

68. Barhoom S, M. Kupiec, Zhao X, Xu JR, Sharon A. (2008) Functional characterization of cgCTR2, a putative vacuole copper transporter that is involved in germination and pathogenicity in Colletotrichum gloeosporioides. Eukaryot Cell 7:1098-1108.

69. Ulitsky, I., Shlomi, T., M. Kupiec and R. Shamir (2008) From E-MAPs to module maps: dissecting quantitative genetic interactions using physical interactions. Molec. Systems Biology, in press.

70. Borenstein E., M. Kupiec, M. W. Feldman and E. Ruppin (2008) Large-Scale Reconstruction and Phylogenetic Analysis of Growth Environments and Metabolic Seed Sets. Proc. Natl. Acad. Sci. USA, under revision.

71. Tuller T, Kupiec M. and E. Ruppin (2008) Co-evolution of Conserved Genes and Cellular Processes Across Fungal Species. Molec. Systems Biology, under revision.

72. Tuller T, Kupiec M. and E. Ruppin (2008) Evolutionary Rate and Gene Expression Across Different Brain Tissues. Trends in Genetics, submitted.

73. Schonbrun, M., Laor D., Lopez-Maury-L., Bahler J., M. Kupiec and Weisman R. (2008) The TORC2 complex regulates DNA damage response, gene silencing, and telomere length maintenance. Science, submitted.

74. Romano, G.H., I. Ulitsky, R. Shamir, Y. Gurevich and M. Kupiec (2008) Dissection of a complex genetic network determining natural genetic variability. PLoS Genetics, submitted.

75. Yosef N., M. Kupiec, Ruppin E. and Sharan R. (2008) A complex-centric view of protein network evolution. Molec. Syst. Biology, submitted.

76. Mitchell, A, G. H. Romano, M. Kupiec, O. Dahan and Y. Pilpel (2008) Prediction of subsequent environmental changes by both eukaryotic and prokaryotic micro-organisms enhances adaptation to natural habitats. Nature, under revision.

B. CHAPTERS IN BOOKS

1. Kupiec, M., Y. Nevo, C. Melamed, C. Roitgrund, and A. Parket. (1992) Homologous recombination between Ty elements in yeast. In: Viruses of Fungi and Lower Eukaryotes. Y. Koltin and M.J. Leibowitz, eds. Marcel Dekker,

New York.

2. Kupiec, M., B. Byers, R E. Esposito, and A. P Mitchell. (1997) Meiosis and sporulation in Saccharomyces cerevisiae. In: The Molecular and Cellular Biology of the Yeast Saccharomyces. Pringle, J. R., J. R. Broach, and E. W. Jones, eds., pp. 889-1036. Cold Spring Harbor Laboratory Press, New York.

C. REVIEWS

1. Petes, T., P. Detloff, S. Jinks-Robertson, S. Judd, M. Kupiec, D. Nag, A. Stapleton, L. Symington, A. Vincent, M. White. (1990) Recombination in yeast and the recombinant DNA technology. Genome 31: 536-540.

2. Kupiec, M., and R. Steinlauf. (1997) Damage-induced ectopic recombination in the yeast Saccharomyces cerevisiae. Mutat. Res. 384: 33-44.

3. Kupiec, M. (2000) Damage-induced recombination in the yeast Saccharomyces cerevisiae. Mutat. Res. 451: 91-105.

4. Koren, A., Ben-Aroya, S. and M. Kupiec (2002) The control of meiotic recombination initiation: a role for the environment? Current Genetics 42: 129- 139.

5. Aylon, Y. and M. Kupiec (2004) New insights into the mechanism of homologous recombination. Mutat. Res. Rev. 566: 231-248.

6. Aylon, Y. and M. Kupiec (2004) DSB Repair: the yeast paradigm. DNA Repair, 3: 797:815.

7. Ben-Aroya, S. and M. Kupiec (2005) The Elg1 Replication Factor C-like complex: a novel guardian of genome stability. DNA repair 4: 409-417.

Prof. Martin Kupiec, PI

Rivka Steilauf, M.Sc.

Lab Manager
B.Sc - Life Sciences The Hebrew University, Jerusalem, Israel.
M.Sc – Microbiology, Hadassah School of Medicine, The Hebrew University, Jerusalem, Israel.
Supervision – Dr. E Shapira.
Thesis title : Amyloidosis in mice ; isolation, characterization and antigenic properties.
1971 – 1989 – Senior Research technician, Prof. Koltin's laboratory. Genetics department,.
Dept of Genetics, Tel Aviv University, Ramat Aviv, Tel Aviv, 69978
1989 – date. Lab Manager, Prof. Martin Kupiec's research group.
Dept of Molecular Microbiology and Biotechnology, Tel Aviv University, Ramat Aviv, Tel Aviv, 69978

Recent Publications:
1. Ben-Aroya S, Koren A, Liefshitz B, Steinlauf R, Kupiec M., " ELG1, a yeast gene required for genome stability, forms a complex related to replication factor C." PNAS, 2003.

2. Koren A, Ben-Aroya S, Steinlauf R, Kupiec M., "Pitfalls of the synthetic lethality screen in Saccharomyces cerevisiae: an improved design". Curr Genet. 2003.

3. Friedl AA, Liefshitz B, Steinlauf R, Kupiec M., "Deletion of the SRS2 gene suppresses elevated recombination and DNA damage sensitivity in rad5 and rad18 mutants of Saccharomyces cerevisiae.", Mutat Res. 2001.

4. Jablonovich Z, Liefshitz B, Steinlauf R, Kupiec M., " Characterization of the role played by the RAD59 gene of Saccharomyces cerevisiae in ectopic recombination", Curr Genet. 1999.

5. Liefshitz B, Steinlauf R, Friedl A, Eckardt-Schupp F, Kupiec M., " Genetic interactions between mutants of the 'error-prone' repair group of Saccharomyces cerevisiae and their effect on recombination and mutagenesis", Mutat Res. 1998.

Batia Liefshitz

Ronit Weisman, Ph.D.

I am a Faculty member in the Natural Life Sciences at the Open University, Israel. I conduct my research at Tel Aviv University. My main research focus on the TOR (Target of Rapamycin) signaling pathway, using fission yeast as a model organism.

Research interests:
- TOR-dependent signaling pathways
- Control of cellular growth and divisions
- Cellular responses to nutritional stress
- Cellular response to DNA damaging conditions

Recent Publications:
1. Weisman, R. and Choder, M. (2001) The fission yeast TOR homologue, tor1+, is required for the response to starvation and other stresses via a conserved serine. J. Biol. Chem. 276: 7027-7032
2. Weisman, R., Finkelstein, S. and Choder, M.(2001) Rapamycin blocks sexual development in fission yeast through inhibition of the cellular function of an FKBP12 homologue. J. Biol. Chem. 276: 24736-24742
3. Weisman, R. (2003) The fission yeast TOR proteins and rapamycin response: an unexpected tale. (Invited review) Curr. Top. Microbiol. Immunol. 279:85-95.
4. Weisman, R., Roitburg I., Nahari, T. and Kupiec, M. (2005) Regulation of leucine uptake by tor1+ in fission yeast is sensitive to rapamycin. Genetics 169:539-550.
5. Weisman, R., Roitburg I., Schonburn M., Harari R. and Kupiec, M. (2007) Opposite effects of Tor1 and Tor2 on nitrogen starvation responses in fission yeast. Genetics 175:1153-1162
6. Schonburn M. Laor D. Maury L., Bahler J., Kupiec, M. and Weisman R. (2009) The TORC2 complex regulates DNA damage response, gene silencing and maintenance of telomere length (Mol. Cell Biol. In press)

Gal Hagit Romano

I am currently a Post Doctorat student under a joint supervision of Prof. Ron Shamir and Martin Kupiec.
I participated in the Interdepartmental Masters Program (M.Sc.) in Life and Medical Sciences for Excellent Academic Achievers and countinued to the direct Ph.D program.

Research interests:
- Genetic dissection of Quantitative Trait Loci
- The effect of stress on telomeres length
- Systems Biology

Publications:
1. Mitchell A, Romano GH, Groisman B, Yona A, Dekel E, Kupiec M, Dahan O and Pilpel Y. "Adaptive prediction of environmental changes by microorganisms" Nature, 2009.
2. Gal-Hagit Romano, Yonat Gurevich, Ofer Lavi, Igor Ulitsky, Ron Shamir and Martin Kupiec. "Different sets of QTLs influence fitness variation in yeast". MSB, 2009, in revision.

Neta Agmon

I am currently a PhD student.
I did my M.Sc. in genetic in Prof. Danny Segal lab, thesis titeled: "The mechanism of formation of extrachromosomal circular DNA and its replication by rolling circle" .

Research interests:
Choice of mechanism for the repair of a Double Strand break in yeast.

Publications:
1. Cohen, S., Agmon, N., Yacobi, K., Mislovati, M., and Segal, D. ”Evidence for Rolling Circle replication of Tandem Genes in Drosophila”. Nucleic Acids Research, 2005, Vol. 33, No. 14: 4519-4526.
2. Agmon, N., Pur, S., Liefshitz, B., and Kupiec, M., "Analysis of repair mechanism choice during homologous recombination". Nucleic Acids Research, 2009. 3. Cohen, S., Agmon, N., Sobol, O., and Segal D.” Extrachromosomal circles of satellite repeats and 5S ribosomal DNA in human cells and their possible rolling circle replication”. Mobile DNA, 2009, in press.
4. Ben-Aroya, S., Agmon, N., Yuen, K., Kwok, T., McManus, K., Kupiec, M., and Hieter, P. "Evolutionarily conserved role for proteasomal subunits in maintaining chromosome stability". PLoS Genetics, in revision.

Adi Barzel

I am a Ph.D student and a graduate of the interdisciplinary program for Excellent Students.

Research interests:
- Gene therapy: non-viral gene targeting via homing endonucleases
- The distribution and evolution of homing endonucleases
- Homologous recombination- How do homologous DNA molecules get together for recombination?

Publications:
1. Barzel A and Kupiec M, Finding a match: how do homologous sequences get together for recombination? (2008) Nature Reviews Genetics
2. Barzel A et al. 2 Patents pending posted on May 2009

Miriam Schonbrun

I am a Ph.D student under the joint supervision of Prof. Martin Kupiec and Dr. Ronit Weisman.

Research interests:
- TOR as a central regulator of cellular growth and division
- Involvement of the TOR signaling pathway in the cellular response to DNA damage

Publications:
1. Schonbrun M, Laor D., Lopez-Maury L., Bahler J., Kupiec M. and Weisman R. (2009). TOR complex 2 controls gene silencing, telomere length maintenance and survival under DNA damaging conditions. MCB. (PMID: 19546237)
2. Weisman R, Roitburg I, Schonbrun M, Harari R, Kupiec M. (2007). Opposite effects of Tor1 and Tor2 on nitrogen starvation responses in fission yeast. Genetics, 175(3):1153-62.

Oren Parnas

I am currently a Ph.D student in the Program for Excellent Students.

Research interests:
My research focuses on PCNA (proliferating cell nuclear antigen). PCNA is a key factor in DNA replication and repair due to its ability to slide along the DNA, thus providing a platform to recruit proteins that involve in DNA maintenance. In my research I am exploring how PCNA is regulated and in what circumstances the alternative clamp loaders loads and unloads it to the DNA. I am interest in several processes that affect genomic stability: DNA repair, DNA replication, chromatin remodeling and sister chromatid cohesion.

Publications:
Parnas O, Zipin-Roitman A, Mazor Y, Liefshitz B, Ben-Aroya S, Kupiec M. “The ELG1 clamp loader plays a role in sister chromatid cohesion.” PLoS ONE. May 2009

Adi Zipin-Roitman

I am currently a Post Doctorat student.

Research interests:
My research focuses on DNA damage repair during replication in the budding yeast Saccharomyces cerevisiae: ELG1 collaboration with PCNA in maintaining replication fork stability

Publications:
1. Lifshitz V, Chen-Levi L, Zipin-Roitman A, Meshel T, Sagi-Assif O, Levi-Nissenbaum O, Witz IP, Yron I. The tumour microenvironment regulates components of the fucose biosynthesis pathways in colorectal cancer cells. In: Gasche C, Gassull M, Herrerias Gutierrez JM, Monterio E, editors. Intestinal Inflammation and Colorectal Cancer. Heidelberg: Springer. 2007, vol:158:294-305.
2. Adi Zipin-Roitman, Tsipi Meshel, Orit Sagi-Assif, Bruria Shalmon, Camila Avivi, Raphael M. Pfeffer, Isaac P. Witz, Adit Ben-Baruch. CXCL10 promotes invasion-related properties in human colorectal carcinoma cells, Cancer Research, 67, 3396-3405 (2007).
3. Adi Zipin, Orlev Levy-Nissenbaum, Rinat Eshel, Tsipi Meshel, Orit Sagi-Assif, and Isaac P. Witz The Fucose Generating FX Enzyme and Selectin Ligands in Colorectal Cancer: A Functional Axis. Proceedings of the 3rd International Conference on Tumor Microenvironment: Progression, Therapy and Prevention. Prague, Czech Republic. Isaac P. Witz, Ed., Medimond Editore, S.r.l., Bologna, Italy, 63-70 (2005).
4. Adi Zipin, Mira Israeli-Amit, Tsipi Meshel, Orit Sagi-Assif, Ilana Yron, Veronica Lifshitz, Eran Bacharach, Nechama I. Smorodinsky, Ariel Many, Peter A. Czernilofsky, Donald L. Morton and Isaac P. Witz. Tumor-microenvironment interactions. The fucose-generating FX enzyme controls adhesive properties of colorectal cancer cells. Cancer Research, 64, 6571-6578 (2004).
5. Parnas O, Zipin-Roitman A, Mazor Y, Liefshitz B, Ben-Aroya S, Kupiec M. “The ELG1 clamp loader plays a role in sister chromatid cohesion.” PLoS ONE. May 2009

Taly Ben-Shitrit

I am currently PhD student.

Research interests:
- Telomere length maintenance mechanism.
- System biology.

Lior Ungar

I am currently a MD/PhD student.

Research interests:
- Telomere length maintenance mechanism.
- Image processing tools developing.
- System biology.
- TOR complex and telomeres.
- RNA processing.

Publications:
1. Rafi Shachar, Lior Ungar, Martin Kupiec, Eytan Ruppin & Roded Sharan, A systems-level approach to mapping the telomere length maintenance gene circuitry, Molecular System Biology 2008.
2. Nir Yosef*, Lior Ungar*, Einat Zalckvar, Adi Kimchi, Martin Kupiec, Eytan Ruppin, & Roded Sharan, Toward accurate reconstruction of functional protein networks, Molecular System Biology 2009 (*These authors contributed equally to this work)
3. Lior Ungar, Nir Yosef, Yael Sella, Roded Sharan, Eytan Ruppin and Martin Kupiec , A genome-wide screen for essential yeast genes that affect telomere length maintenance, Nucleic Acid Research 2009

Dana Laor

I am currently a PhD student.

Research interests:
The TOR pathway regulates cellular growth, gene silencing and telomere length maintenance in Schizosaccharomyces pombe.

Publications:
Schonbrun M, Laor D., Lopez-Maury L., Bahler J., Kupiec M. and Weisman R. ”The TORC2 complex regulates DNA damage response, gene silencing, and telomere length maintenance.” Molecular and Cellular Biology (2009) 29:4584-4594.

Linda Rubinstein

I am a Ph.D. student
I finished my M.Sc. Degree with honors at the Hebrew University of Jerusalem

Research interests:
- Genetic analysis of genes with telomeric phenotype
- Finding new mechanisms effecting telomere length

Shiri Pur

I am a research assistant at the lab.
I finished my M.Sc.

Research interests:
TOR and recombination

Publications:
Agmon, N., Pur, S., Liefshitz, B., and Kupiec, M., "Analysis of repair mechanism choice during homologous recombination". Nucleic Acids Research, 2009.

Einat Shachar

I am a research assistant at the lab.
I finished my M.Sc degree with honors in biology, the Faculty of Agriculture, department of Entomology, the Hebrew University of Jerusalem.

Research interests:
- Gene therapy: non-viral gene targeting via homing endonucleases

Publications:
Wilson, M., Moshitzky, P., Laor, E., Ghanim, M., Horowitz, A.R. Morin, S. "Reversal of resistance to pyriproxyfen in the Q biotype of Bemisia tabaci (Hemiptera: Aleyrodidae)." Pest Management Science (2006).

Yaniv Harari

I am a Master student

Research interests:
- The effect of stress on telomere length.
- Finding an unknown component of the telomere length regulation process.

Camila Savoia Sigismondi

I am a Master student.

Research interests:
Genetic interactions between genes involved in a genetic network of alkali stress resistance.

Masha Kolesnikov

I am a Master student

Research interests:
The subject I'm working on is the involvement of TOR1 in gene silencing in the yeast Schizosaccharomyces pombe.

Alex Bronshtein

I am a Master student

Research interests:
Understanding the impact of the ELG1 protein in the following processes: DNA repair, DNA replication, chromatin remodeling and sister chromatid cohesion.