The major focus of this project is to understand how cells monitor and repair DNA damage. Defects in either the surveillance or repair of damaged DNA can lead to chromosomal instability and cancer. For example, inherited disorders affecting cellular responses to DNA damage, such as ataxia telangiectasia are characterized by increased susceptibility to lymphoid cancer, extreme radiation sensitivity and immunodeficiency. We are generating knockout and transgenic mouse models that have specific defects in DNA double strand break (DSB) repair through the genetic manipulation of the major players that mediate homologous recombination and non-homologous end joining DNA repair pathways. We have characterized mice that were defective in non-homologous end joining, the major pathway for repairing DSBs in mammalian cells and provided evidence for a novel mechanism for HR restoration through the inactivation of proteins functioning in an alternate DNA repair pathway called non-homologous end joining (NHEJ). Loss of the NHEJ proteins 53BP1, PTIP and RIF1 restored normal HR activity in BRCA1 deficient cells, and rendered these cells resistant to PARPi. A major aim of this research project is to understand how altering the balance between NHEJ and HR pathways can be exploited to overcome the Achilles heel of acquired resistance in breast cancer treatment. In addition to showing that one mechanism of chemoresistance is through the re-establishment of homologous recombination in the tumor, we have made the recent finding that replication fork stability can also promote survival and drive resistance to chemotherapy in BRCA1/2-mutant cancers. We are currently exploring the use of existing panels of BRCA1/2-mutant mouse and human breast carcinomas with primary or acquired chemotherapy resistance, to directly test the hypothesis that complex processes involving replication fork stability promotes survival and drives resistance to chemotherapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
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Basic Sciences
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Greer, Yoshimi Endo; Gao, Bo; Yang, Yingzi et al. (2017) Lack of Casein Kinase 1 Delta Promotes Genomic Instability - The Accumulation of DNA Damage and Down-Regulation of Checkpoint Kinase 1. PLoS One 12:e0170903
Yazinski, Stephanie A; Comaills, Valentine; Buisson, Rémi et al. (2017) ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells. Genes Dev 31:318-332
Tubbs, Anthony; Nussenzweig, André (2017) Endogenous DNA Damage as a Source of Genomic Instability in Cancer. Cell 168:644-656
Canela, Andres; Maman, Yaakov; Jung, Seolkyoung et al. (2017) Genome Organization Drives Chromosome Fragility. Cell 170:507-521.e18
Salewsky, Bastian; Hildebrand, Gabriele; Rothe, Susanne et al. (2016) Directed Alternative Splicing in Nijmegen Breakage Syndrome: Proof of Principle Concerning Its Therapeutical Application. Mol Ther 24:117-24
Skau, Colleen T; Fischer, Robert S; Gurel, Pinar et al. (2016) FMN2 Makes Perinuclear Actin to Protect Nuclei during Confined Migration and Promote Metastasis. Cell 167:1571-1585.e18
Zong, Dali; Chaudhuri, Arnab Ray; Nussenzweig, André (2016) More end resection is not merrier. Nat Struct Mol Biol 23:699-701
Chaudhuri, Arnab Ray; Callen, Elsa; Ding, Xia et al. (2016) Erratum: Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature 539:456
Nieto-Soler, Maria; Morgado-Palacin, Isabel; Lafarga, Vanesa et al. (2016) Efficacy of ATR inhibitors as single agents in Ewing sarcoma. Oncotarget 7:58759-58767
Li, Minxing; Cole, Francesca; Patel, Dharm S et al. (2016) 53BP1 ablation rescues genomic instability in mice expressing 'RING-less' BRCA1. EMBO Rep 17:1532-1541

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