Andre Nussenzweig, Ph.D.

NIH Distinguished Investigator

Laboratory of Genome Integrity

NCI/CCR

Building 37, Room 1106A
Bethesda, MD 20892-4254

240-760-7607

nussenza@mail.nih.gov

Research Topics

The Laboratory of Genome Integrity: December 2014 Seated (L to R): Amanda Day, Subhadra Banerjee, Ludmila Krymskaya, Christelle Harly, David McCurdy, Avinash Bhandoola (Senior Investigator), Andre Nussenzweig (Laboratory Chief), Henry Chen, Andres Canela Rodriguez and Nancy Wong Standing (L to R): Karen Wolcott, Sam John, Anthony Tubbs, Caiyi Li, Pulak Ranjan Nath, Dali Zong, Arnab Ray Chaudhuri, Margarida Santos, Khadidiatou Waye, Elsa Callen Moreu (Staff Scientist), Andre Stanlie, Aysegul Ergen and Robert Faryabi

Genomic instability is a hallmark of cancer. Central to a cell's ability to maintain genomic stability are systems that monitor and repair DNA double strand breaks (DSBs). DSBs occur during normal DNA replication, in response to chemotherapeutic agents, and during physiological reactions including meiotic recombination in germ cells and antigen receptor rearrangements in lymphocytes. If not rapidly and faithfully repaired, DSBs can also be substrates for aberrant chromosomal translocations, which promote cancer.

The focus of the Recombination Unit is to understand the mechanisms by which all cell types monitor and repair DSBs. Our research has 3 major goals: 1) Determine the mechanisms by which cells detect, signal and repair DSBs; 2) Elucidate the mechanisms by which oncogenic translocations form; 3) determine the influence of chromatin structure on the maintenance of genomic stability. Our past achievements in these areas form the basis of ongoing and future research.

DNA Damage Signaling and Repair

One aim of the previous proposal was to gain a better mechanistic understanding of the interplay between DNA damage detection and signaling in vivo. To this end, we determined the biological impact of impaired Nbs1 function at the cellular and organismal level, we gained a better mechanistic understanding of the pathways that activate ATM, we discovered that ATM prevents un-repaired DNA breaks from propagating from one generation to the next, we found that replicative stress mediated by the ATR kinase contributes to aging and we described a DNA-Pkcs dependent pathway that regulates DNA repair and activation of p53 in the absence of ATM. One major current effort is to study the interplay between NHEJ, HR and cell cycle checkpoints in maintaining genomic stability.

Oncogenic Translocations

Activation induced cytodine deaminase (AID) is an enzyme that is essential for somatic hypermutation and class-switching. In 2005, we devised a method to monitor chromosome translocations between c-myc and IgH in vitro. We then performed a series of studies aimed at understanding pathways that normally survey and protect against AID-dependent DNA damage: First, we determined that the catalytic activity of AID is required for generation of c-myc/IgH translocations, we then showed that AID is required for the chromosomal breaks in c-myc, and that AID in fact produces DSBs in many non-Ig genes, which in turn promote B cell lymphomagenesis. During the course of these studies we also described DNA damage- and oncogenic stress-induced checkpoints that protect against AID-dependent DNA damage. One of the earliest responses to AID induced damage is the formation of nuclear foci of 53BP1. Besides playing an essential role in CSR, we discovered a more general function for 53BP1 in maintaining genomic stability during long-range joining of DNA breaks. Although 53BP1 is a tumor suppressor, we found that the embryonic lethality and tumorigenesis induced by Brca1 mutation can be alleviated by 53BP1 deletion. One major current effort is to understand the mechanism by which loss of 53BP1 prevents translocations and tumorigenesis in Brca1 mutant cells and regulates class switching.

Role of Chromatin Structure in Maintaining Genomic Stability

Another important challenge is to understand the effects of chromatin on DNA repair, and how this 'chromatin barrier' is relieved to enable DSB repair. In 2005, we devised a sensitive method to examine the changes in chromatin structure in living cells at sites of DSBs. We discovered that while DSBs remain relatively immobile over time, chromatin undergoes a marked reorganization (decondensation) in response to DSB. More recently, we have been studying the chromatin changes critical for immunogloblulin class switch recombination (CSR). We have discovered that a component of the histone methyltransferase complex called PTIP is essential for CSR by promoting histone H3 lysine 4 tri-methylation and transcription of switch regions. In AIM 3, we propose to further investigate the relationship between histone methylation, transcription and DNA repair during antigen receptor rearrangements.

Biography

Dr. Nussenzweig received his Ph.D. in Physics from Yale University in 1989. He completed his postdoctoral training in atomic physics in Paris with Dr. Serge Haroche, who was awarded the Nobel prize in Physics in 2012. Subsequently, Dr. Nussenzweig became a Research Fellow at Memorial Sloan-Kettering Cancer Center prior to joining the Experimental Immunology Branch as a tenure track investigator in 1998. Dr. Nussenzweig received tenure at NIH in 2003. In 2011, Dr. Nussenzweig established a new department at NCI called the Laboratory of Genome Integrity. Dr. Nussenzweig is an elected member of the European Molecular Biology Organization and a National Institutes of Health Distinguished Investigator.

Selected Publications

  1. Canela A, Sridharan S, Sciascia N, Tubbs A, Meltzer P, Sleckman BP, Nussenzweig A. DNA Breaks and End Resection Measured Genome-wide by End Sequencing. Mol Cell. 2016;63(5):898-911.

  2. Ray Chaudhuri A, Callen E, Ding X, Gogola E, Duarte AA, Lee JE, Wong N, Lafarga V, Calvo JA, Panzarino NJ, John S, Day A, Crespo AV, Shen B, Starnes LM, de Ruiter JR, Daniel JA, Konstantinopoulos PA, Cortez D, Cantor SB, Fernandez-Capetillo O, Ge K, Jonkers J, Rottenberg S, Sharan SK, Nussenzweig A. Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature. 2016;535(7612):382-7.

  3. Barlow JH, Faryabi RB, Callén E, Wong N, Malhowski A, Chen HT, Gutierrez-Cruz G, Sun HW, McKinnon P, Wright G, Casellas R, Robbiani DF, Staudt L, Fernandez-Capetillo O, Nussenzweig A. Identification of early replicating fragile sites that contribute to genome instability. Cell. 2013;152(3):620-32.

  4. Bunting SF, Callén E, Wong N, Chen HT, Polato F, Gunn A, Bothmer A, Feldhahn N, Fernandez-Capetillo O, Cao L, Xu X, Deng CX, Finkel T, Nussenzweig M, Stark JM, Nussenzweig A. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell. 2010;141(2):243-54.

  5. Callén E, Jankovic M, Difilippantonio S, Daniel JA, Chen HT, Celeste A, Pellegrini M, McBride K, Wangsa D, Bredemeyer AL, Sleckman BP, Ried T, Nussenzweig M, Nussenzweig A. ATM prevents the persistence and propagation of chromosome breaks in lymphocytes. Cell. 2007;130(1):63-75.


This page was last updated on June 20th, 2017