The genetic lesions that promote tumorigenesis, including chromosomal rearrangements, are generated primarily by illegitimate DNA repair. In this renewal application, we will continue to investigate the pathological consequences of aberrant DNA double-strand break (DSB) repair. This highly collaborative and integrated program will elucidate how DNA sequence, chromatin accessibility and nuclear organization influence the fate and pathological outcomes of DSBs in a cell type and cell cycle dependent manner. We will continue to use a combination of genetics in yeast and mouse models, biochemistry and cell biology. The application of next generation technologies together with high-throughput genomics approaches provides an unprecedented wealth of information about genomic instability in cancer genomes. We propose to leverage our multifaceted experimental approach with the strong genomics and computational biology components that pervade the Program. Drs. Rabadan and Baer will study mutation signatures - the statistically enriched patterns of DNA substitutions and rearrangements common across tumors - associated with specific BRCA1 deficiencies. They will also characterize mutation signatures generated by the other three Projects. Collectively these data will help deconvolute the complex mutational landscape of human tumors. Drs. Symington and Ciccia will address the nature of the initiating DNA lesions resulting in chromosome rearrangements, focusing on DNA replication errors in repair-deficient yeast and genome-edited mammalian cells. Dr. Sha will connect chromatin accessibility, locally and globally, with its propensity to break and yield translocations; pathological translocations at the immunoglobulin and T cell receptor loci during lymphocyte maturation fuel lymphoma development. Specifically, Dr. Zha will elucidate how ATM deficiencies favor translocations in a cell type and cell cycle dependent manner. Finally, Drs. Gautier and Gottesman will study how the spatial organization of the nucleus modulates DNA repair. Specifically, they will determine how nuclear actin and WASP, the gene mutated in Wiskott-Aldrich Syndrome, enables resection and influences chromosome translocations following DSBs or genotoxic lesions triggered by topoisomerase inhibition. The four Projects will be supported by two scientific Cores. All leaders and co-leaders have a strong history and record of productive collaboration.

Public Health Relevance

Illegitimate DNA double-strand break (DSB) repair fuels genomic instability and subsequent tumorigenic transformation. The goal of this program is to understand how the nature of DNA lesions, their chromatin context, cell type and cell cycle phase in which they arise influence their pathological outcomes: mutations and chromosome rearrangements.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Witkin, Keren L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
Schools of Medicine
New York
United States
Zip Code
Yu, Tai-Yuan; Kimble, Michael T; Symington, Lorraine S (2018) Sae2 antagonizes Rad9 accumulation at DNA double-strand breaks to attenuate checkpoint signaling and facilitate end resection. Proc Natl Acad Sci U S A 115:E11961-E11969
Oh, Julyun; Lee, So Jung; Rothstein, Rodney et al. (2018) Xrs2 and Tel1 Independently Contribute to MR-Mediated DNA Tethering and Replisome Stability. Cell Rep 25:1681-1692.e4
Billing, David; Horiguchi, Michiko; Wu-Baer, Foon et al. (2018) The BRCT Domains of the BRCA1 and BARD1 Tumor Suppressors Differentially Regulate Homology-Directed Repair and Stalled Fork Protection. Mol Cell 72:127-139.e8
Schrank, Benjamin R; Aparicio, Tomas; Li, Yinyin et al. (2018) Nuclear ARP2/3 drives DNA break clustering for homology-directed repair. Nature 559:61-66
Gnügge, Robert; Oh, Julyun; Symington, Lorraine S (2018) Processing of DNA Double-Strand Breaks in Yeast. Methods Enzymol 600:1-24
Crowe, Jennifer L; Shao, Zhengping; Wang, Xiaobin S et al. (2018) Kinase-dependent structural role of DNA-PKcs during immunoglobulin class switch recombination. Proc Natl Acad Sci U S A 115:8615-8620
Gnügge, Robert; Symington, Lorraine S (2017) Keeping it real: MRX-Sae2 clipping of natural substrates. Genes Dev 31:2311-2312
Liu, Xiangyu; Shao, Zhengping; Jiang, Wenxia et al. (2017) PAXX promotes KU accumulation at DNA breaks and is essential for end-joining in XLF-deficient mice. Nat Commun 8:13816
Kato, Niyo; Kawasoe, Yoshitaka; Williams, Hannah et al. (2017) Sensing and Processing of DNA Interstrand Crosslinks by the Mismatch Repair Pathway. Cell Rep 21:1375-1385
Aparicio, Tomas; Gautier, Jean (2016) BRCA1-CtIP interaction in the repair of DNA double-strand breaks. Mol Cell Oncol 3:e1169343

Showing the most recent 10 out of 25 publications