Skip to Content

'
Randy J. Legerski, Ph.D.

Present Title & Affiliation

Primary Appointment

Professor, Department of Genetics, Division of Basic Science Research, The University of Texas M. D. Anderson Cancer Center, Houston, TX

Research Interests

  • Cellular responses to DNA damage
  • DNA repair
  • Cell cycle checkpoint signaling

The overall objective of my laboratory is the study of molecular mechanisms of cellular responses to DNA damage in mammalian systems. We are particularly interested in the relationship between these pathways and the degenerative processes of carcinogenesis and aging in humans. Our current focus is on the mechanisms of repair of interstrand cross-links in DNA. Repair of interstrand cross-links is a significant topic for human health since important chemotherapeutic agents used against cancer and other diseases can induce these lesions. In addition, food sources and mammalian metabolism can produce cross-linking agents that lead to DNA damage and genomic instability in cells. Genetic studies, primarily in yeast, have shown that homologous recombination is a primary pathway of cross-link repair; however, the early steps of damage recognition and processing of these lesions are still undefined. To investigate these pathways, we have developed a mammalian cell-free biochemical assay that has allowed us to begin identifying factors involved in this pathway and to elucidate the repair mechanisms. Using this in vitro assay, we have purified several factors involved in the initial stages of cross-link repair, and their characterization is currently a major focus of the laboratory. Our long-term goal is to completely reconstitute the mammalian interstrand cross-link repair pathway.

In addition to our biochemical studies, we are also focusing on the characterization of a small mammalian gene family whose homologue in yeast is specifically involved in cross-link repair. The snm1 (sensitivity to nitrogen mustard) mutant of Saccharomyces cerevisiae was first identified in a screen for strains sensitive to bifunctional alkylating agents. We have identified three mammalian homologues of this gene, SNM1, SNM1B and Artemis, and are currently characterizing their functions in mammalian cells. In constrast to the role scSNM1 we have found that SNM1 and Artemis are involved in mediating cell cycle checkpoints in mammalian cells in response to both DNA damage and mitotic stress. We are continuing to use biochemical, molecular biological and genetic approaches, including gene-targeting strategies in the mouse, to elucidate the function of the mammalian SNM1 genes.

Office Address

Phone: (713) 834-6363
Email: rlegersk@mdanderson.org

Education & Training

Degree-Granting Education

1977 University of Houston, Houston, TX, PHD, Biophysical Chemistry

Selected Publications

Peer-Reviewed Original Research Articles
1. Zhang N, Kaur R, Akhter S, Legerski R. Cdc5L Interacts with ATR and Is Required for the S Phase Cell Cycle Checkpoint. EMBO Reports. In Press.
2. Wang H, Zhang X, Geng L, Teng L, Legerski R. Artemis Regulates Cell Cycle Recovery from the S Phase Checkpoint by Promoting Degradation of Cyclin E. J Biol Chem 284(27):18236-43, 7/2009. e-Pub 5/2009. PMID: 19423708.
3. Zhang X, Zhu Y, Geng L, Wang H, and Legerski RJ. Artemis is a Negative Regulator of p53 in Response to Oxidative Stress. Oncogene 28(22). e-Pub 4/2009. PMCID: PMC2692457.
4. Bae JB, Mukhopadhyay SS, Liu L, Zhang N, Tan J, Akhter S, Liu X, Shen X, Li L, Legerski RJ. Snm1B/Apollo Mediates Replication Fork Collapse and S Phase Checkpoint Activation in Response to DNA Interstrand Cross-Links. Oncogene 27(37):5045-56, 8/2008. e-Pub 5/2008. PMID: 18469862.
5. Geng L, Zhang X, Zheng S, Legerski RJ. Artemis links ATM to G2/M checkpoint recovery via regulation of Cdk1-cyclin B. Mol Cell Biol 27(7):2625-35, 4/2007. e-Pub 1/2007. PMCID: PMC1899901.
6. Zheng H, Wang X, Legerski RJ, Glazer PM, Li L. Repair of DNA interstrand cross-links: interactions between homology-dependent and homology-independent pathways. DNA Repair (Amst) 5(5):566-74, 5/2006. e-Pub 3/2006. PMID: 16569514.
7. Zhang N, Kaur R, Lu X, Shen X, Li L, Legerski RJ. The Pso4 mRNA splicing and DNA repair complex interacts with WRN for processing of DNA interstrand cross-links. J Biol Chem 280(49):40559-67, 12/2005. PMID: 16223718.
8. Ahkter S, Richie CT, Zhang N, Behringer RR, Zhu C, Legerski RJ. Snm1-deficient mice exhibit accelerated tumorigenesis and susceptibility to infection. Mol Cell Biol 25(2):10071-8, 11/2005. PMID: 16260620.
9. Akhter S, Richie CT, Deng JM, Brey E, Zhang X, Patrick C, Jr, Behringer RR, Legerski RJ. Deficiency in SNM1 abolishes an early mitotic checkpoint induced by spindle stress. Mol Cell Biol 24(23):10448-55, 12/2004. PMID: 15542852.
10. Zhang X, Succi J, Feng Z, Prithivirajsingh S, Story MD, Legerski RJ. Artemis is a phosphorylation target of ATM and ATR and is involved in the G2/M DNA damage checkpoint response. Mol Cell Biol 24(20):9207-20, 10/2004. PMID: 15456891.
11. Richie CT, Peterson C, Lu T, Hittelman WN, Carpenter PB, Legerski RJ. hSnm1 colocalizes and physically associates with 53BP1 before and after DNA damage. Mol Cell Biol 22(24):8635-47, 12/2002. PMID: 12446782.
12. Zhang N, Lu X, Zhang X, Peterson CA, Legerski RJ. hMutSbeta is required for the recognition and uncoupling of psoralen interstrand cross-links in vitro. Mol Cell Biol 22(7):2388-97, 4/2002. PMID: 11884621.
13. Li L, Peterson CA, Lu X, Wei P, Legerski RJ. Interstrand cross-links induce DNA synthesis in damaged and undamaged plasmids in mammalian cell extracts. Mol Cell Biol 19(8):5619-30, 8/1999. PMID: 10409751.
14. Henning KA, Li L, Iyer N, McDaniel LD, Reagan MS, Legerski R, Schultz RA, Stefanini M, Lehmann AR, Mayne LV, Friedberg EC. The Cockayne syndrome group A gene encodes a WD repeat protein that interacts with CSB protein and a subunit of RNA polymerase II TFIIH. Cell 82(4):555-64, 8/1995. PMID: 7664335.
15. Li L, Elledge SJ, Peterson CA, Bales ES, Legerski RJ. Specific association between the human DNA repair proteins XPA and ERCC1. Proc Natl Acad Sci U S A 91(11):5012-6, 5/1994. PMID: 8197174.
16. Li L, Bales ES, Peterson CA, Legerski RJ. Characterization of molecular defects in xeroderma pigmentosum group C. Nat Genet 5(4):413-7, 12/1993. PMID: 8298653.
17. Legerski R, Peterson C. Expression cloning of a human DNA repair gene involved in xeroderma pigmentosum group C. Nature 359(6390):70-3, 9/1992. PMID: 1522891.
18. Liu P, Legerski R, Siciliano MJ. Isolation of human transcribed sequences from human-rodent somatic cell hybrids. Science 246(4931):813-5, 11/1989. PMID: 2479099.

Last updated: 7/15/2009