Ayegul is currently an interagency oncology taskforce fellow (IOTF) at the FDA.
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.
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.
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.
Selected Recent Publications
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.
|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)|
Ayegul is currently an interagency oncology taskforce fellow (IOTF) at the FDA.
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
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).
National Eye Institute
National Institutes of Health
Frederica is a biologist at the National Eye Institute (NEI), NIH.
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.
Science Policy Analyst
Friends of Cancer Research
Marina is a science policy analyst at Friends of Cancer Research, a cancer advocacy organization based in Washington, D.C.
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 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
Most recently, Simone served as a principal scientist at the Center for Advanced Preclinical Research at NCI-Frederick.
After completing her postdoctoral fellowship in 2007, Manuela now holds an independent investigator position at the University of Rome.
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 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