- Molecular and Human Genetics
- Baylor College of Medicine
- Houston, TX, US
- Dan L Duncan Comprehensive Cancer Center
- Baylor College of Medicine
- Houston, Texas, United States
- PhD from Copernicus University and Jacques Monod Institute
- Postdoctoral Fellowship at Brandeis University
Honors & Awards
- Michael E. DeBakey, M.D., Excellence in Research Award
- President’s Award for Innovative Research
- Genome Instability
- Molecular mechanisms and regulation of DNA recombination
Our group aims to understand how cells repair damage to their DNA and how deficiency in this process results in genome instability, cancer, many hereditary disorders, infertility and ageing. We are particularly interested in how cells repair chromosomal double-strand breaks, one of the most dangerous types of DNA lesions.
Chromosome breaks occur spontaneously in cells and have to be repaired faithfully by recombination to maintain genome integrity and to warrant cell survival. Interestingly some cells induce programmed chromosome breaks. For example, germ cells generate over one hundred DNA breaks to induce meiotic recombination resulting in new combinations of alleles in gametes; and lymphocytes induce DNA breaks at the V(D)J locus that is essential for generating diverse antibodies. DNA recombination is also highly relevant to cancer treatment as the most prevalent therapy, radiotherapy, relies on inducing DNA breakage. Understanding the basic features of DNA repair and recombination and identifying the proteins involved in these processes may point the way to new diagnostic or therapeutic approaches for cancer and other diseases.
Eukaryotes exhibit a remarkable degree of conservation with respect to DNA repair, recombination and replication. This offers great potential for using model organisms to study these processes. Our laboratory employs both budding and fission yeast which share a high degree of similarity with many biological processes in human cells. These model organisms provide numerous diverse experimental advantages including genetic, molecular, functional genomics, and next generation sequencing based approaches for screening and characterizing new DNA repair proteins. We can successfully use yeast to decipher the exact mechanism of genome instability, a strategy that is not possible in other organisms due to the lack of cellular approaches.
In our experimental systems chromosomal breaks are induced by nucleases that generate site-specific and single per genome DNA breaks. The elegance of these systems is that DNA breaks occur in all cells synchronously, allowing every step of the DNA repair process to be monitored. We can also extend our findings of these mechanisms to learn more about the molecular functions of DNA repair proteins. Specifically, our work provides insight to the function of homologous proteins and DNA repair processes in human and other organisms.
Current Research Directions
Mechanism and regulation of DNA recombination pathways
DNA breaks can be repaired by many different pathways of recombination, some of which are mutagenic and normally suppressed. We aim to understand the mechanism of high and low fidelity repair and decipher how cells suppress the usage of low fidelity repair pathways. Decreased fidelity of DNA repair and genome instability are hallmarks of cancer and cellular ageing. Thus we anticipate that our work will provide new insight into how faulty DNA repair events are upregulated and contribute to tumorigenesis and/or aging.
Mechanism and regulation of DNA break end resection
Most DNA repair and DNA damage signaling proteins recognize single-stranded DNA generated at chromosomal break sites. Therefore, duplex DNA break ends have to first be processed to single strands for successful repair and for proper sensing and signaling of DNA damage. Our group identified and characterized several enzymes responsible for this initial step of DNA break repair, providing a foundation for similar discoveries in mammalian cells. Resection dictates the choice of break repair pathway, and can impact repair efficiency, fidelity, and repair template choice. Therefore, DNA break end resection is very tightly regulated, both positively and negatively, to ensure proper repair. Our goals are to better understand the mechanism and regulation of this process.
Large insertions at DNA breaks
Recently we identified the first mutant that shows frequent insertions of relatively large DNA fragments into DNA breaks. In this mutant lacking one of the DNA nucleases important for replication, virtually any piece of any chromosome can jump into DNA breaks resulting in gene duplications. This type of genome rearrangement is common in cancer, but interestingly similarly sized insertions at the V(D)J locus can stimulate antibody diversification in human cells. We aim to better understand the mechanism of these insertions and to screen for additional mutants with similar phenotypes to identify other key factors in this process.
- Yu Y, Pham N, Xia B, Papusha A, Wang G, Yan Z, Peng G, Chen K, Ira G. "Dna2 nuclease deficiency results in large and complex DNA insertions at chromosomal breaks." Nature. 2018;564:287–290.
- Mayle R, Campbell IM, Beck CR, Yang Y, Wilson M, Shaw CA, Bjergbaek L, Lupski JR, Ira G. "Mus81 and converging forks limit the mutagenicity of replication fork breakage." Science. 2015 August 14;349:742-747.
- Wilson MA, Kwon Y, Xu Y, Chung WH, Chi P, Niu H, Mayle R, Chen X, Malkova A, Sung P, Ira G. "Pif1 helicase and Polδ promote recombination-coupled DNA synthesis via bubble migration.." Nature. 2013;502(7471):393-6. Pubmed PMID: 24025768
- Chen X, Cui D, Papusha A, Zhang X, Chu CD, Tang J, Chen K, Pan X, Ira G. "The Fun30 nucleosome remodeller promotes resection of DNA double-strand break ends.." Nature. 2012 September 27;489(7417):576-80. Pubmed PMID: 22960743
- Chen X, Niu H, Chung WH, Zhu Z, Papusha A, Shim EY, Lee SE, Sung P, Ira G. "Cell cycle regulation of DNA double-strand break end resection by Cdk1-dependent Dna2 phosphorylation.." Nat. Struct. Mol. Biol.. 2011;18(9):1015-9. Pubmed PMID: 21841787
- Niu H, Chung WH, Zhu Z, Kwon Y, Zhao W, Chi P, Prakash R, Seong C, Liu D, Lu L, Ira G, Sung P. "Mechanism of the ATP-dependent DNA end-resection machinery from Saccharomyces cerevisiae.." Nature. 2010 September 2;467(7311):108-11. Pubmed PMID: 20811460
- Prakash R, Satory D, Dray E, Papusha A, Scheller J, Kramer W, Krejci L, Klein H, Haber JE, Sung P, Ira G. "Yeast Mph1 helicase dissociates Rad51-made D-loops: implications for crossover control in mitotic recombination.." Genes Dev.. 2009 January 1;23(1):67-79. Pubmed PMID: 19136626
- Zhu Z, Chung WH, Shim EY, Lee SE, Ira G. "Sgs1 helicase and two nucleases Dna2 and Exo1 resect DNA double-strand break ends.." Cell. 2008 September 19;134(6):981-94. Pubmed PMID: 18805091