DNA Repair and Maintenance of Genome Stability
Max-Delbrück Center for Molecular Medicine (MDC)
Tel: +49 30 9406 3846
Genomic DNA is constantly under the assault of both endogenous and exogenous damaging sources. As a result, our cells experience a multitude of DNA lesions every day. Among all the different types of DNA damage, DNA double-strand breaks (DSBs) represent one of the most dangerous lesions since they may lead to cancer-prone genome alterations. DSBs arise following exposure to ionizing radiation or radio-mimetic chemicals, but they are also generated as a by-product of normal cellular metabolism, with the majority of spontaneous DSBs originating during DNA replication. In addition to these accidental breaks, DSBs can be introduced in a programmed manner as intermediates of physiological processes such as Class Switch Recombination (CSR) in B lymphocytes, a deletional recombination reaction that changes the constant region of the antibody molecule, altering its effector function. Accurate repair of both accidental and programmed DSBs is therefore crucial to ensure both the preservation of genome integrity and the generation of genome diversity.
The research in my laboratory aims at addressing a fundamental question in Life Sciences: What are the molecular mechanisms that ensure both the integrity and diversity of our genome by modulating DSB formation and by steering their repair towards the appropriate physiological outcome? We employ mature B lymphocytes as ideal model system since in addition to experiencing programmed DNA breaks during CSR, these cells are highly proliferative and therefore susceptible to stochastic replication-associated damage, thus allowing us to comprehensively investigate the mechanisms ensuring genome diversity and stability, and their relationship.
- Delgado-Benito V, Rosen DB, Wang Q, Gazumyan A, Pai JA, Oliveira TY, Sundaravinayagam D, Zhang W, Andreani M, Keller L, Kieffer-Kwon KR, Pękowska A, Jung S, Driesner M, Subbotin RI, Casellas R, Chait BT, Nussenzweig MC, Di Virgilio M. (2018) The Chromatin Reader ZMYND8 Regulates Igh Enhancers to Promote Immunoglobulin Class Switch Recombination. Mol Cell 72(4): 636-649.
- Callen E, Di Virgilio M, Kruhlak MJ, Nieto-Soler M, Wong N, Chen HT, Faryabi RB, Polato F, Santos M, Starnes LM, Wesemann DR, Lee JE, Tubbs A, Sleckman BP, Daniel JA, Ge K, Alt FW, Fernandez-Capetillo O, Nussenzweig MC, Nussenzweig A. (2013) 53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions. Cell 153(6):1266-80.
- Di Virgilio M, Callen E, Yamane A, Zhang W, Jankovic M, Gitlin AD, Feldhahn N, Resch W, Oliveira TY, Chait BT, Nussenzweig A, Casellas R, Robbiani DF, Nussenzweig MC. (2013) Rif1 prevents resection of DNA breaks and promotes immunoglobulin class switching. Science 339(6120):652-3.