Andre Nussenzweig, Ph.D.

Andre  Nussenzweig, Ph.D.
Chief
NIH Distinguished Investigator
Head, Molecular Recombination Section

Dr. Nussenzweig is a leading contributor to the study of mechanisms that maintain genomic stability and prevent cancer. His laboratory has elucidated many fundamental features of DNA damage and repair proteins and revealed the critical role they play in both normal and pathogenic states. Ongoing studies have emphasized the importance of DNA repair pathways as drivers of specific hematological malignancies and as contributors to chemoresistance/sensitivity in breast and ovarian cancers. The goal of his program is to use hypothesis-driven approaches to develop therapeutic strategies in the treatment of cancers.

Areas of Expertise
1) genomic Instability, 2) DNA damage/repair, 3) breast/ovarian cancers, 4) recombination/replication, 5) chromosomal translocations, 6) adult/pediatric leukemias

Contact Info

Andre Nussenzweig, Ph.D.
Center for Cancer Research
National Cancer Institute
Building 37, Room 1106A
Bethesda, MD 20892-4254
Ph: 240-760-7607
Fax: 240-541-4489
nussenza@mail.nih.gov

LGI Branch 2014

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.

Scientific Focus Areas:
Cancer Biology, Chromosome Biology, Genetics and Genomics, Immunology, Stem Cell Biology
View Dr. Nussenzweig's PubMed Summary.

Selected Recent Publications

  1. Canela A, Maman Y, Jung S, Wong N, Callen E, Day A, Kieffer-Kwon K, Pekowska A, Zhang H, Rao S, Huang S, Mckinnon PJ, Aplan PD, Pommier Y, Lieberman Aiden E, Casellas R, Nussenzweig A
    Cell. 170(3): 507–521, 2017. [ Journal Article ]
  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.
    Nature. 535(7612): 382-7, 2016. [ Journal Article ]
  3. Santos MA, Faryabi RB, Ergen AV, Day AM, Malhowski A, Canela A, Onozawa M, Lee J, Callen E, Gutierrez-Martinez P, Chen H, Wong N, Finkel N, Deshpande A, Sharrow S, Rossi DJ, Ito K, Ge K, Aplan PD, Armstrong SA, Nussenzweig A.
    Nature. 514(7520): 107-11, 2014. [ Journal Article ]
  4. 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.
    Cell. 153: 1266-80, 2013. [ Journal Article ]
  5. 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.
    Cell. 152: 620-32, 2013. [ Journal Article ]

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.

Position Number of Positions Contact E-mail Contact Name Contact Phone
Postdoctoral Fellow/Staff Scientist 1 sam.john@nih.gov Sam John 240-760-7601
Name Position
Elsa Callen Moreu Ph.D. Staff Scientist
Hua Tang (Henry) Chen Ph.D. Research Biologist
Amanda Day Animal Technician (Contr)
Yaakov Maman, Ph.D. Staff Scientist
Jacob Paiano Predoctoral Fellow (Graduate Student)
Andres Canela Rodriguez Ph.D. Research Fellow
Nicholas Sciascia B.S. Predoctoral Fellow (IRTA)
Kenta Shinoda Ph.D. Postdoctoral Fellow (Visiting)
Andre Stanlie Ph.D. Postdoctoral Fellow (Visiting)
Anthony Tubbs Ph.D. Postdoctoral Fellow (CRTA)
Sriram Vakulabaranam Sridharan Ph.D. Postdoctoral Fellow (Visiting)
Niek Van Wietmarschen Ph.D. Postdoctoral Fellow (Visiting)
Nancy Wong M.S. Research Biologist
Dali Zong Ph.D Postdoctoral Fellow (CRTA)
Arnab Ray Chaudhuri Post-doctoral fellow 2013-2017

Arnab has started his own research program on all things related to replication and genome instability in his new position as Principal Investigator and Group Leader in the Department of Molecular Genetics at Erasmus University Medical Center in Rotterdam, Netherlands.  

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Aysegul Ergen Postdoctoral Fellow (2012-2015)

Ayegul is currently an interagency oncology taskforce fellow (IOTF) at the FDA. 

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Robert (Babak) Faryabi, Ph.D. Research Fellow (2010 - 2015)

Assistant Professor of Pathology and Medicine
Perelman School of Medicine
University of Pennsylvania
Member, Abramson Family Cancer Research Institute

Babak started his research program in the fall of 2015 at the University of Pennsylvania. The focus of his lab is to explore the genome-wide signatures of replicative stress. As a member of Center for Personalized Diagnostics, his lab is also interested in developing computational oncology frameworks to enrich the clinical significance of diagnostic tumor genomics.

More about Babak and his research at http://faryabib.github.io

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Margarida A. Santos, Ph.D. Research Fellow (2008 - 2015)

Margarida has started her own research program on stem cell renewal and the role of DNA damage and repair proteins at the University of Texas M.D. Anderson Cancer Center in Houston, TX. She is the recipient of an award from Cancer Prevention and Research Institute of Texas (CPRIT).

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Frederica Polato, Ph.D. Research Fellow (2006 - 2014)

Biologist
National Eye Institute
National Institutes of Health

Frederica is a biologist at the National Eye Institute (NEI), NIH.

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Jacqueline Barlow, Ph.D. Postdoctoral Fellow (2008 - 2014)
Assistant Professor
Department of Microbiology and Molecular Genetics
College of Biological Sciences
University of California, Davis

Jackie started her own research program in the fall of 2014 at the University of California, Davis in Sacramento. Jackie will be continuing her exciting work on early replicating fragile sites and their contribution to genome stability.


Marina Kozak, Ph.D. Postdoctoral Fellow (2010 - 2012)

Science Policy Analyst
Friends of Cancer Research
Washington, D.C.

Marina is a science policy analyst at Friends of Cancer Research, a cancer advocacy organization based in Washington, D.C.


Sam Bunting, Ph.D. Postdoctoral Fellow (2006 - 2012)
Assistant Professor
Department of Molecular Biology and Biochemistry
Rutgers University

Sam completed his postdoctoral training in 2012, received a NIH Pathway to Independence Award (K99) and is currently an assistant professor in the Department of Molecular Biology and Biochemistry at Rutgers University. You can find out more about Sam’s research program at http://molbiosci.rutgers.edu/faculty/bunting.html. He is interested in aspects of DNA repair pathway selection and cell-type specific DNA damage responses.


Jeremy A. Daniel, Ph.D. Postdoctoral Fellow (2006 - 2011)
Associate Professor and Group Leader
Chromatin Structure & Function Group
The Novo Nordisk Foundation
Center for Protein Research
University of Copenhagen

Jeremy is currently associate professor and group leader at the University of Copenhagen’s Novo Nordisk Foundation Center for Protein Research. Jeremy completed his postdoctoral training in 2011 and has been competitive for funding from both the NIH and the Swedish Research Council. Jeremy uses biochemical and genetic approaches to study the contribution of chromatin modifying complexes in genome stability and cancer. More about Jeremy and his research at http://www.cpr.ku.dk/staff/385400/csf/?pure=en/persons/421746


Simone Difilippantonio, Ph.D. Research Fellow, Staff Scientist (2000 - 2008)
Principal Scientist
Center for Advanced Preclinical Research
Leidos Biomedical Research, Inc.
National Cancer Institute at Frederick

Most recently, Simone served as a principal scientist at the Center for Advanced Preclinical Research at NCI-Frederick.


Manuela Pellegrini, Ph.D. Postdoctoral Fellow (2004 - 2007)
Principal Investigator
Department of Public Health and Cellular Biology
University of Rome Tor Vergata

After completing her postdoctoral fellowship in 2007, Manuela now holds an independent investigator position at the University of Rome.


Alicia Lee, Ph.D. Predoctoral Fellow (2002 - 2006)

Alicia Lee obtained her Ph.D. from the NIH Oxford-Cambridge Scholars Program in 2006. She was co-mentored by Dr. Stephen Jackson (Cambridge University) and by Dr. Nussenzweig.


Oscar Fernandez-Capetillo, Ph.D., Postdoctoral Fellow (2001 - 2004)
Senior Group Leader and Tenured Investigator
Genomic Instability Group, Molecular Oncology Program
Spanish National Cancer Research Center

Oscar is an HMMI International Early Career Scientist and has won numerous national and international awards and grants, including the Eppendorf Award for Young Investigators, EMBO Young Investigator, and an ERC Starting Grant, amongst others. Oscar was in the Nussenzweig lab from 2001-2004. His scientific interests are numerous and varied but are generally focused in the area of the cellular response to DNA damage. More about Oscar at http://www.cnio.es/ing/grupos/plantillas/presentacion.asp?grupo=50004266


Quinn Tai Summer Student (2014 - 2015)
Nadia Finkel Summer Student (2014 - 2015)

Protocol for END-seq, an unbiased and genome-wide approach that maps DNA double-strand breaks (DSBs) with precision and sensitivity. END-seq provides a snapshot of DNA ends genome-wide, which can be utilized for understanding genome-editing specificities and the influence of chromatin on a variety of physiological and pathological processes.

Canela et. al., Mol Cell. 2016 Sep 1;63(5):898-911