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.
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.
|Aparicio, Tomas; Gautier, Jean (2016) BRCA1-CtIP interaction in the repair of DNA double-strand breaks. Mol Cell Oncol 3:e1169343|
|Oh, Julyun; Al-Zain, Amr; Cannavo, Elda et al. (2016) Xrs2 Dependent and Independent Functions of the Mre11-Rad50 Complex. Mol Cell 64:405-415|
|Yamamoto, Kenta; Wang, Jiguang; Sprinzen, Lisa et al. (2016) Kinase-dead ATM protein is highly oncogenic and can be preferentially targeted by Topo-isomerase I inhibitors. Elife 5:|
|Aparicio, Tomas; Baer, Richard; Gottesman, Max et al. (2016) MRN, CtIP, and BRCA1 mediate repair of topoisomerase II-DNA adducts. J Cell Biol 212:399-408|
|Symington, Lorraine S (2016) Mechanism and regulation of DNA end resection in eukaryotes. Crit Rev Biochem Mol Biol 51:195-212|
|Reczek, Colleen R; Shakya, Reena; Miteva, Yana et al. (2016) The DNA resection protein CtIP promotes mammary tumorigenesis. Oncotarget 7:32172-83|
|Sfeir, Agnel; Symington, Lorraine S (2015) Microhomology-Mediated End Joining: A Back-up Survival Mechanism or Dedicated Pathway? Trends Biochem Sci 40:701-14|
|Jiang, Wenxia; Crowe, Jennifer L; Liu, Xiangyu et al. (2015) Differential phosphorylation of DNA-PKcs regulates the interplay between end-processing and end-ligation during nonhomologous end-joining. Mol Cell 58:172-85|
|Chen, Huan; Donnianni, Roberto A; Handa, Naofumi et al. (2015) Sae2 promotes DNA damage resistance by removing the Mre11-Rad50-Xrs2 complex from DNA and attenuating Rad53 signaling. Proc Natl Acad Sci U S A 112:E1880-7|
|Deng, Sarah K; Chen, Huan; Symington, Lorraine S (2015) Replication protein A prevents promiscuous annealing between short sequence homologies: Implications for genome integrity. Bioessays 37:305-13|
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