DNA double-strand break (DSB) repair prevents persistent DNA damage, counteracts genome instability and suppresses tumor development. However, DSB repair also has the potential to produce oncogenic chromosome translocations and rearrangements. This highly integrated program will elucidate the mechanism and regulation of DSB repair initiation and its impact on DSB repair choice, chromosome translocation and cancer development in model of lymphoma and breast cancer. In particular, the program will investigate the regulation of microhomology-mediated end-joining (MMEJ), a pathogenic form of DSB repair responsible for a significant fraction of tumorigenic chromosome translocations. Preliminary studies from all projects focusing on DNA processing and CtIP have generated a focused and cohesive program. Dr. Symington will use genetic analysis to assess how DNA resection affects MMEJ and to investigate the competition between MMEJ and other modes of DSB repair. Dr. Symington will also develop sensitive physical resection assays in mammalian cells, a technology which is notably lacking at present. Drs. Gautier and Gottesman will study the mechanism(s) that generate persistent, short ssDNA overhangs at DSBs, an intermediate involved in MMEJ. Their studies will focus on the role of CtIP, a protein involved in initiation of DNA resection. In the third project, Drs. Zha and Dalla-Favera will evaluate the role of CtIP in repair of programmed DSBs during lymphocyte development and malignancy. They will also test the hypothesis that CtIP mediates, at least in part, the oncogenic function of c-Myc including its undefined role in genomic instability. Dr. Baer, will determine how CtIP facilitates breast tumor development in p53-deficient mice and will test whether CtIP loss can also suppress basal-like breast cancer in BRCA1-deficient mice. Finally, he will evaluate the potential role of CtIP in Myc-driven breast tumor development. To accomplish these goals, the projects will rely extensively on three interlinked cores: administrative, molecular analysis of genomic instability and pathology. The project and core leaders have a very strong history of collaboration, joint efforts in training and common interests in genome stability and the mechanisms of its loss in cancer.

Public Health Relevance

Chromosome translocations play a significant role in cancer development. They frequently arise from a pathogenic form of DNA repair that uses short single-strand DNA intermediates with microhomologies (MH). The goals of this program are to understand how processing of the 5'DNA strand of a double-strand break generates these toxic DNA intermediates and how they are converted into chromosome translocations causing tumor development.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA174653-01A1
Application #
8608844
Study Section
Special Emphasis Panel ()
Program Officer
Pelroy, Richard
Project Start
2014-04-08
Project End
2019-03-31
Budget Start
2014-04-08
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$1,778,566
Indirect Cost
$666,962
Name
Columbia University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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
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
Gnügge, Robert; Symington, Lorraine S (2017) Keeping it real: MRX-Sae2 clipping of natural substrates. Genes Dev 31:2311-2312
Aparicio, Tomas; Gautier, Jean (2016) BRCA1-CtIP interaction in the repair of DNA double-strand breaks. Mol Cell Oncol 3:e1169343

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