Large-scale genomic studies of human tumors have uncovered a series of characteristic ?mutation signatures?; i.e., statistically enriched patterns of DNA substitutions and rearrangements common across tumors. While some of these signatures are associated with particular cancer subtypes, known genotoxic insults, and/or rough mutational patterns arising from specific DNA repair defects, most remain uncharacterized without known biological correlates. To determine the mechanisms by which mutation signatures arise, we will initially focus on triple-negative breast cancers (TNBCs) with lesions in the BRCA1 tumor suppressor pathway. Recent studies have identified at least five distinct mutation signatures in TNBCs. However, we do not know if additional signatures exist, nor do we understand the molecular mechanisms by which these signatures are generated. BRCA1 acts to preserve genome integrity through multiple processes, including homology-directed repair (HDR) and stalled fork protection (SFP), and it does so in association with a number of distinct protein partners. Thus, the mutation signatures associated with TNBC may reflect the loss of particular BRCA1 pathway functions and/or defects in other as yet unidentified DNA repair factors. To address these issues, we will combine expertise in computation analysis of genomic data and the molecular biology of DNA repair to 1) elucidate the molecular mechanisms responsible for TNBC mutation signatures, and 2) determine the full spectrum of mutation signatures associated with TNBC patients bearing pathogenic lesions in the BRCA1 pathway.

Public Health Relevance

Genomic instability, a major driving force of cancer initiation and progression, generates unique ?mutation signatures? that are characteristic of specific types of human cancer. To elucidate how these mutation signatures arise during tumor development, this study will focus on triple-negative breast cancer (TNBC), a highly aggressive malignancy characterized by lesions in the BRCA1 tumor suppression pathway. In particular, the full spectrum of TNBC mutation signatures will be defined and the molecular mechanisms by which these signatures arise will be elucidated.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA174653-06
Application #
9855791
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
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
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
Reczek, Colleen R; Shakya, Reena; Miteva, Yana et al. (2016) The DNA resection protein CtIP promotes mammary tumorigenesis. Oncotarget 7:32172-83

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