Human breast tumors typically display high levels of chromosomal rearrangements, most of which harbor sequence microhomologies (MH) at their junctions. The presence of these MHs suggests that tumor associated chromosome aberrations may arise when double-strand DNA breaks (DSBs) are repaired illegitimately by microhomology-mediated end-joining (MMEJ) rather than preferred modes of DSB repair, such as non-homologous end-joining (NHEJ) or homology-directed repair (HDR). This intriguing idea is supported by recent evidence that the CtlP protein, a key mediator of DNA resection, is essential for MMEJ, and that CtIP inactivation markedly suppresses the formation of chromosome translocations. Woman with germline mutations ofthe BRCA1 tumor suppressor gene often develop basal-like breast carcinoma, an especially lethal subtype of human breast cancer characterized by extensive chromosomal instability. Previously, we reported that the BRCT repeats of the BRCAI polypeptide interact with CtIP and that this interaction is ablated by tumorigenic BRCA1 missense mutations. Subsequently, we used conditional mutagenesis to show that basal-like breast tumors can be induced in mice by mammary-specific Brca1inactivation and that the BRCT repeats are essential for both the chromosome stability and tumor suppression functions of BRCAI. To ascertain whether CtIP also contributes to tumor suppression, we recently examined the effects of mammary-specific Ctip inactivation in mice. Remarkably, Ctip ablation strongly suppressed breast cancer formation in p53-deficient animals. By providing the first experimental evidence that Ctip can promote tumorigenesis, this result is consistent with the central hypothesis of this Program;that DSB repair by CtlP-dependent MMEJ can lead to oncogenic chromosomal rearrangements. Therefore, to explore this hypothesis. Project 4 will determine 1) how CtIP facilitates breast cancer development, 2) whether CtIP is required for development of basal-like breast cancer, and 3) whether Ctip is involved in Myc-driven breast cancer.

Public Health Relevance

Aberrant chromosomal rearrangements are implicated in most human malignancies, including breast cancer. Our preliminary data show that depletion of CtlP, a DNA repair protein that promotes the formation of chromosome translocations, dramatically reduces breast tumor development in mice. By defining how Ctip promotes chromosomal rearrangements and breast carcinogenesis, the proposed project should identify valuable molecular targets and new strategies for cancer prevention and therapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel ()
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University
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