Prof. Martin Kupiec
Ph.D.: 1985, Hebrew University Jerusalem
Phone: (Office) +972-3-640-9031
(Fax) +972-3-640-9407
E-mail: martin@post.tau.ac.il
Room#: Green 216
Member's portrait
  Personal Information
  Research Interests
  Selected Publications
  Students and Lab Members

Personal Information
Education

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.
2003-2013 Editor, FEMS Microbiology Reviews.
2006-2009 Board of Directors, The Genetic Society of Israel.
2007 The Tel Aviv University Prize for Research Excellence.
2008-present The Pasha Gol Chair for Applied Microbiology
2010-present Editor, Genetics Research International.
2011-present Editorial Board member, Molecular and Cellular Biology.
2011-present Elected Fellow of the American Academy of Microbiology.
2011-present Director, The Joan and Haim Constantiner Center for Molecular Genetics.
2012-present Editor, Journal of Fungal Genomics and Biology.
2012-present Editorial Board Member, Open Access Genetics.
2012-present Editorial Board Member, Open Access Genetics.
2012-present Editorial Board Member, Open Access Genetics.
2013-present President, Genetic Society of Israel.


Research Interests

 

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?

• How does the tethering of chromosomes to the nuclear envelope affect the ability of broken chromosomes to search for their “partners” for recombination? And HOW do you SEARCH for partners with similar sequences?
• What is the minimal length required for efficient ectopic homologous recombination? (Hint: very little!)

 

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?

The mammalian copy of ELG1 has been found to be involved in Fanconi Anemia, a cancer-promoting hereditary human disease and in sporadic cancer. In mice, KO of ELG1 leads to tumors. What can we learn about cancer-preventing mechanisms by analyzing Elg1? Is it involved in a Fanconi-like mechanism in yeast? (Hint: yes!)

 

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. Two systematic screens, using collections of yeast mutants, resulted in the identification of ~400 genes that affect telomere length. Mutations in half of them cause telomere shortening, whereas mutations in the others 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 several 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.

Recently, we have found that environmental stresses and signals can also affect telomere length. Since we have, for the first time, the list of all genes affecting a complex trait (telomere length) AND a list of environmental factors affecting the same trait, we are in a perfect position to study the interphase between nature and nurture (genome and environment), a central question in Biology that could not be addressed molecularly up to now.

For echoes of this story in the popular press, see:
http://www.aftau.org/site/News2?page=NewsArticle&id=19499

http://www.haaretz.com/weekend/magazine/.premium-1.552996

and in Hebrew:

http://www.haaretz.co.il/magazine/the-edge/.premium-1.2136474

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?


 

OTHER SUBJECTS:

• How is the genome organized? Are genes randomly distributed? (Hint: no!)
• Does a deletion of one gene affect the expression of its neighbor? And if so, is this important for our conclusions about genetic phenotypes and interactions? (Hint: yes!)

• Can we use our knowledge about homologous recombination to improve Gene Therapy methodologies? (Hint: yes!)
• How is translation regulated? Is the codon usage randomly organized? (Hint: no!)
• Does the response to DNA damage occur only at the RNA level? (Hint: no, it also affects translation!)
• QTLs: Can we map all the genes affecting single traits? How do genes interact to establish a certain phenotype? (Hint: it’s complicated!)

Lab pictures

 

 

 
 

Selected Publications

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

47. 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.

48. 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.

49. 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.

50. 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.

51. 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.

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

53. 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.

54. 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.

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

56.  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.

57. 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.

58. 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.

59. 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.

60. 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.

61. 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.

62. 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.

63. 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.

64. 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.

65. 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.

66. 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.

67. 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.

68. 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.

69. 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.

70. 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.

71. 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.

72. 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 4:209.

73. 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, 105:14482-14487.

74. Tuller T., Kupiec M. and E. Ruppin (2008) Evolutionary Rate and Gene Expression Across Different Brain Tissues. Genome Biol. 9:R142.

75. Tuller T, Kupiec M. and E. Ruppin (2009) Co-evolutionary networks of genes and cellular processes across fungal species. Genome Biol. 10:R48.

76. Schonbrun, M., Laor D., Lopez-Maury-L., Bahler J., M. Kupiec and Weisman R. (2009) The TORC2 complex regulates DNA damage response, gene silencing, and telomere length maintenance. Mol. Cell. Biol., 29(16):4584-4594.

77. Yosef N., Ungar L., Zalckvar E., Kimchi A., Kupiec M., Ruppin E., Sharan R. (2009) Toward accurate reconstruction of functional protein networks. Mol Syst Biol. 5:248.

78. Mitchell A., Romano G.H., Groisman B., Yona A., Dekel E., Kupiec M., Dahan O. and Y. Pilpel (2009) Adaptive prediction of environmental changes by microorganisms. Nature 460(7252):220-224. News and views in: Nature (2009) 460(7252):181 and Cell 138:409 (2009).

79. Mazor, Y. and M. Kupiec (2009) Developmentally regulated MAPK pathways modulate heterochromatin in Saccharomyces cerevisiae. Nucl. Acid Research 37(14):4839-4849.

80. Ungar, L., Sela, Y., Yosef, N., Sharan, R. Ruppin, E. and M. Kupiec (2009) A genome-wide screen for essential yeast genes that affect telomere length maintenance. Nucl. Acid Research 37(12):3840-3849.

81. Yosef N., M. Kupiec, Ruppin E. and Sharan R. (2009) A complex-centric view of protein network evolution. Nucleic Acid Research 37(12):e88.

82. Fridman, V., Gerson-Gurwitz A., Movshovitz N., Kupiec, M. and L. Gheber (2009) Midzone organization restricts interpolar microtubule plus-end dynamics during spindle elongation. EMBO Reports, 10: 387-393.

83. Tuller, T., Rubinstein U., Bar D., Gurevitch M., Ruppin E. and M. Kupiec (2009) Higher-order genomic organization of cellular functions in yeast. J Comput Biol. 16: 303-316.

84. Parnas O, Zipin-Roitman A, Mazor Y, Liefshitz B, Ben-Aroya S, M. Kupiec (2009) The ELG1 clamp loader plays a role in sister chromatid cohesion. PLoS ONE 4: e5497.

85. Agmon, N., Pur, S., Liefshitz, B. and M. Kupiec (2009) Analysis of repair mechanism choice during homologous recombination. Nucl. Acid Res. 37: 5081-5092.

86. Tuller, T., Ruppin E. and M. Kupiec (2009) Properties of untranslated regions of the S. cerevisiae genome. BMC Genomics, 10: 391-398.

87. Tuller, T. Birin, H., Gophna, U., Kupiec, M. and E. Ruppin (2010) Reconstructing Ancestral Genomic Sequences by Co-Evolution. Genome Research 20: 122-132.

88. Ben-Aroya, S., Agmon N., Yuen, K., Kwok, T, McManus K., Kupiec M. and P. Hieter (2010) Proteasome nuclear activity affects chromosome stability by controlling the turnover of Mms22, a protein important for DNA repair. PLoS Genetics 6: e1000852.

89. Romano, G.H., Gurvich Y., Lavi O., Ulitsky I., Shamir, R. and M. Kupiec (2010) Different sets of QTLs affect fitness variation in yeast. Molec. Systems Biology 6:346-357.

90. Tuller, T., Waldman Y., Kupiec M. and E. Ruppin (2010) Translation Efficiency Is Determined By Both Codon Bias and Folding Energy. Proc. Natl. Acad. Sci. USA 107:3645-3650.

91. Gat-Viks, I., Meller, R., Kupiec, M. and R. Shamir (2010) Understanding gene sequence variation in the context of transcription regulation in yeast. PLoS Genetics 6: e1000800.

92. Tuller, T., Felder, Y. and M. Kupiec (2010). Discovering local patterns of co-evolution: computational aspects and biological examples. BMC Bioinformatics 11: 43- 62.

93. Parnas O., Zipin-Roitman, A., Pfander, B., Liefshitz, B., Mazor, Y., Ben-Aroya, S., Jentsch, S. and M. Kupiec (2010) Elg1, an alternative subunit of the RFC clamp loader, preferentially interacts with SUMOylated PCNA. EMBO J. 29: 2611 - 2622.

94. Parnas, O. and M. Kupiec (2010) Establishment of sister chromatid cohesion: The role of the clamp loaders. Cell Cycle 9: 4615. (Invited comment on: Maradeo et al., “Rfc5p regulates alternate RFC complex functions in sister chromatid pairing reactions in budding yeast”. Cell Cycle 2010; 9:4370–4378.

95. Tuller, T., Birin H., Kupiec, M., and Eytan Ruppin (2010) Reconstructing Ancestral Genomic Sequences by Co-Evolution: Formal Denitions, Computational Issues, and Biological Examples. Journal of Computational Biology, 17:1327-1344.

96. Barzel A, Naor A, Privman E, Kupiec M. and U. Gophna (2011) Homing endonucleases residing within inteins: evolutionary puzzles awaiting genetic solutions. Biochem Soc Trans. 39:169-73.

97. Zhang X., Kupiec, M., Gophna, U. and T. Tuller (2011) Analysis of Co-evolving Gene Families Using Evolutionarily Reciprocal Orthologous Modules. Genome Biology and Evolution 3:413-423.

98. Barzel, A., Privman, E., Pe’eri, M., Naor, A., Sachar, E., Burstein, D., Lazary, R., Gophna, U., Pupko, T. and M. Kupiec (2011) Native homing endonucleases can target conserved target sites in humans and in animal models. Nucleic Acid Research 39: 6646-6659.

99. Tuller, T., Girshovich, Y., Sella Y., Kreimer A., Freilich S., Kupiec, M., Gophna, U. and E. Ruppin (2011) Association between translation efficiency and horizontal gene transfer within microbial communities. Nucleic Acids Res. 2011 Feb 22.

100. Barzel, A., Obolski U., Gogarten, J.P., Kupiec, M. and Hadany L. (2011) Home and away, the evolutionary dynamics of homing endonucleases. BMC Evol Biology 11: 324.

101. Agmon, N., Yovel, M., Harari, Y., Liefshitz, B. and M. Kupiec (2011) The role of Holliday Junction resolvases in the repair of spontaneous and induced DNA damage. Nucleic Acid Research 39: 7009-7019.

102. Reuveni, S., I. Meilijson, M. Kupiec, E. Ruppin and T. Tuller (2011). Genome-Scale Analysis of Translation Elongation with a Ribosome Flow Model. PLoS Comput Biol. 7(9):e1002127.

103. Parnas, O., Amishay R., Liefshitz, B., Zipin-Roitman A., and M. Kupiec (2011) Elg1, the major subunit of an alternative RFC complex, interacts with SUMO-processing proteins. Cell Cycle 10: 17.

104. Liefshitz, B. and M. Kupiec (2011) The roles of RSC, Rad59 and cohesin in DSB repair. Mol Cell Biol. 2011 Oct;31(19):3921-3. Epub 2011 Aug 15. (invited commentary on Oum et al., “RSC facilitates Rad59-dependent homologous recombination between sister chromatids by promoting cohesin loading at DNA double strand breaks”. Mol Cell Biol. 2011 Oct;31(19):3924-37. Epub 2011 Aug 1)

105. Tuller, T., Veksler, I., Gazit, N., Kupiec, M., Ruppin, E., M. Ziv-Ukelson (2011) Composite effects of gene determinants on the translation speed and density of ribosomes. Genome Biol. 12: R110.

106. Ungar, L., Harari, Y. Toren, A. and M. Kupiec (2011) Tor Complex 1 controls telomere length by regulating the level of Ku. Current Biology 21: 2115-2120.

107. Freilich, S., R. Zarecki, O. Eilam, E.Shtifman-Segal, C.S.Henry, M. Kupiec, U. Gophna, R. Sharan and E. Ruppin (2011) Competitive and cooperative metabolic interactions in bacterial communities. Nature Communications 2:589. doi: 10.1038/ncomms1597.

108. Harari, Y., Rubinstein L. and M. Kupiec (2011) An anti-checkpoint role for Rif1 (invited commentary on Xue et al: “A novel checkpoint and RPA inhibitory pathway regulated by Rif1”. PLoS Genet 7: e1002417) PLoS Genetics e1002421. Epub 2011 Dec 15.

109. Ben-Shitrit, T., Yosef, N., Shemesh, K., Sharan, R., Ruppin, E., and M. Kupiec (2012) Systematic identification of gene annotation errors in the widely used yeast mutation collections. Nature Methods 9: 373-378. News and Views in: Baryshnikova, A. and B. Andrews (2012) Neighboring-gene effect: a genetic uncertainty principle. Nature Methods 9: 341–343.

110. Dominissini, D., Moshitch-Moshkovitz, S.,Schwartz, S., Salmon-Divon, M., Ungar, L., Osenberg, S., Cesarkas, K., Jakob-Hirsch, J., Amariglio, N., Kupiec, M., Sorek, R., and G. Rechavi (2012) Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485: 201-206.

111. Silberberg Y, Gottlieb A, Kupiec M., Ruppin E, Sharan R. (2012) Large-scale elucidation of drug response pathways in humans. J Comput Biol. 19:163-174.

112. Kupiec, M. and R. Weisman (2012) TOR links starvation responses to telomere length maintenance. Cell Cycle 11: 1-4.

113. Gazy, I. and M. Kupiec (2012) The importance of being modified: PCNA modification and DNA damage response. Cell Cycle. 2012 Jul 15;11(14).

114. Mazón G., Lam A.F., Ho C.K., Kupiec M. and L.S. Symington (2012) The Rad1-Rad10 nuclease promotes chromosome translocations between dispersed repeats. Nat. Struct. Mol. Biol. 19: 964-971. nsmb.2359.

115. Yona,A.H., Manor,Y.S., Romano,G.H., Herbst,R.H., Mitchell,A., Kupiec,M., Dahan, O. and Y. Pilpel (2012) Chromosomal duplication is a transient evolutionary solution to stress. Proc. Nat. Acad. Sci. USA 109:21010-21015.

116. Singh, S., Shemesh, K., Liefshitz B. and M. Kupiec (2013) Genetic and physical interactions between the yeast ELG1 gene and orthologs of the Fanconi Anemia pathway. Cell cycle 12:1625-1636.

117. Agmon, N., Liefshitz, B., Zimmer, C., Fabre, E. and M. Kupiec (2013) Effect of nuclear architecture on the efficiency of double-strand break repair. Nature Cell Biology 15: 694-699.

118. Gazy, I. Liefshitz, B., Bronstein, A., Parnas, O., Atias, N., Sharan, R. and M. Kupiec (2013) A genetic screen for high-copy-number suppressors of the synthetic lethality between elg1 and srs2 in yeast. Genes, Genomes and Genetics 3: 917-926.

119. Schonbrun , M., Kolesnikov, M., Kupiec M. and R. Weisman (2013) TORC2 is required to maintain genome stability during S phase in fission yeast. Journal of Biochemical Chemistry 288:19649-19660.

120. Romano, G-H, Harari, Y., Yehuda, T., Podhorzer, A., Rubinstein, L., Shamir, R., Gottlieb, A., Silberberg, Y., Pe’er D., Ruppin, E., Sharan, R. and M. Kupiec (2013) Environmental stresses disrupt telomere length homeostasis. PLoS Genetics, 9(9):e1003721. doi:10.1371/journal.pgen.1003721.

121. Harari, Y., Romano, G.-H., Ungar, L. and M. Kupiec (2013) Nature vs nurture: Interplay between the genetic control of telomere length and environmental factors. Cell Cycle 12:3465-3470.

122. Gazy, I. and M. Kupiec (2013) Genomic instability and repair mediated by common repeated sequences. Proc. Natl. Academy Sci. USA. 110:19664-19665. Comment on Aksenova AY, et al. (2013) Genome rearrangements caused by interstitial telomeric sequences in yeast. Proceedings of the National Academy of Sciences USA 110:19866-19871.

123. Laor, D., Cohen, A., Pasmanik-Chor, M., Oron-Karni, V., Kupiec, M. and R. Weisman (2013) Isp7 is a novel regulator of amino acid uptake in the TOR signaling pathway. Mol. Cell. Biol., in press.

124. Kupiec, M. (2014) Biology of telomeres: lessons from budding yeast. FEMS Microbiology Reviews, in press.

125. Harari, Y. and M. Kupiec (2014) Genome-wide studies in budding yeast dissect the mechanisms that maintain telomere length. Fungal Genomics, in press.



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