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 Nijmegen breakage syndrome and 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. Recently, we characterized mice that were defective in non-homologous end joining, the major pathway for repairing DSBs in mammalian cells. We found that these mice displayed premature aging, a defect in cellular proliferation, a complete block in lymphocyte development and extreme radiation sensitivity. Surprisingly, however, the mice were not prone to cancer. However, a further inactivation of the p53 tumor suppressor gene markedly increased cancer susceptibility, such that these """"""""double knockout"""""""" mice invariably succumbed to B-cell lymphomas that resembled human Burkitt's lymphoma. Other mouse models for DNA double strand break repair are being generating including animals that lack the Nijmegen breakage sydrome protein.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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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
Ray Chaudhuri, Arnab; Callen, Elsa; Ding, Xia et al. (2016) Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature 535:382-7
Starnes, Linda M; Su, Dan; Pikkupeura, Laura M et al. (2016) A PTIP-PA1 subcomplex promotes transcription for IgH class switching independently from the associated MLL3/MLL4 methyltransferase complex. Genes Dev 30:149-63
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Cloutier, Jeffrey M; Mahadevaiah, Shantha K; ElInati, Elias et al. (2015) Histone H2AFX Links Meiotic Chromosome Asynapsis to Prophase I Oocyte Loss in Mammals. PLoS Genet 11:e1005462
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Robbiani, Davide F; Deroubaix, Stephanie; Feldhahn, Niklas et al. (2015) Plasmodium Infection Promotes Genomic Instability and AID-Dependent B Cell Lymphoma. Cell 162:727-37
Canela, Andres; Stanlie, Andre; Nussenzweig, André (2015) Collateral DNA damage produced by genome-editing drones: exception or rule? Mol Cell 58:565-7
Barlow, Jacqueline H; Nussenzweig, André (2014) Replication initiation and genome instability: a crossroads for DNA and RNA synthesis. Cell Mol Life Sci 71:4545-59
Ira, Grzegorz; Nussenzweig, André (2014) A new Riff: Rif1 eats its cake and has it too. EMBO Rep 15:622-4

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