Andre Nussenzweig, Ph.D.

Center for Cancer Research
National Cancer Institute

Building 37, Room 1106A
Bethesda, MD 20892-4254
240-760-7607
240-541-4489
nussenza@mail.nih.gov

Chief

Laboratory of Genome Integrity

NIH Distinguished Investigator

Head, Molecular Recombination Unit

RESEARCH SUMMARY

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

Chromosome Biology

Molecular Mechanisms of Cancer

Genomic Instability

DNA Damage/Repair

Recombination/Replication

Chromosomal Translocations

Research

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

Resources

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.

END-seq: An Unbiased, High-Resolution, and Genome-Wide Approach to Map DNA Double-Strand Breaks and Resection in Human Cells

Wong N, John S, Nussenzweig A, Canela A. Methods Mol Biol. 2021;2153:9-31

https://pubmed.ncbi.nlm.nih.gov/32840769/

END-seq Protocol.pdf

DNA Breaks and End Resection Measured Genome-wide by End Sequencing

Canela A, Sridharan S, Sciascia N, Tubbs A, Meltzer P, Sleckman BP, Nussenzweig A. Mol Cell. 2016; 63:898-911

https://pubmed.ncbi.nlm.nih.gov/27477910/

Mol Cell END-seq Paper.pdf

Protocol for SAR-seq

Synthesis Associated with Repair sequencing - a method to map sites of DNA repair synthesis by sequencing.

Neuronal enhancers are hotspots for DNA single-strand break repair

Wu, W, Hill, SE, Nathan, WJ, Paiano J, Callen E et. al. Nature. 2021; 593:440-444

https://pubmed.ncbi.nlm.nih.gov/33767446/

SAR-seq Protocol.pdf

When the break is just around the loop

Genome Organization Drives Chromosome Fragility

Canela A, Maman Y, Jung S, Wong N, Callen E et. al. Cell. 2017;170:507-521

https://pubmed.ncbi.nlm.nih.gov/28735753

Inside the nucleus, DNA is packed in highly complex structures that help to control which genes are on and off each time. In this video abstract, we explain how this intricate architecture makes specific DNA sites more susceptible to breaks that, if not properly fixed, can lead to cancer.

Structure and repair of replication-coupled DNA breaks

Pavani R, Tripathi V, Vrtis KB, Zong D, Chari R, Callen E, Pankajam AV, Zhen G, Matos-Rodrigues G, Yang J, Wu S, Reginato G, Wu W, Cejka P, Walter JC, Nussenzweig A

Science. eado3867: 2024. [ Journal Article ]

Active DNA demethylation promotes cell fate specification and the DNA damage response

Wang D, Wu W, Callen E, Pavani R, Zolnerowich N, Kodali S, Zong D, Wong N, Noriega S, Nathan WJ, Matos-Rodrigues G, Chari R, Kruhlak MJ, Livak F, Ward M, Caldecott K, Di Stefano B, Nussenzweig A

Science. 378: 983-989, 2022. [ Journal Article ]

Neuronal enhancers are hotspots for DNA single-strand break repair

Wu W, Hill SE, Nathan WJ, Paiano J, Callen E, Wang D, Shinoda K, van Wietmarschen N, Colón-Mercado JM, Zong D, De Pace R, Shih HY, Coon S, Parsadanian M, Pavani R, Hanzlikova H, Park S, Jung SK, McHugh PJ, Canela A, Chen C, Casellas R, Caldecott KW, Ward ME, Nussenzweig A.

Nature. 593: 440-444, 2021. [ Journal Article ]

Repeat expansions confer WRN dependence in microsatellite-unstable cancers

van Wietmarschen N, Sridharan S, Nathan WJ, Tubbs A, Chan EM, Callen E, Wu W, Belinky F, Tripathi V, Wong N, Foster K, Noorbakhsh J, Garimella K, Cruz-Migoni A, Sommers JA, Huang Y, Borah AA, Smith JT, Kalfon J, Kesten N, Fugger K, Walker RL, Dolzhenko E, Eberle MA, Hayward BE, Usdin K, Freudenreich CH, Brosh RM Jr, West SC, McHugh PJ, Meltzer PS, Bass AJ, Nussenzweig A.

Nature. 586:292-298: 292-298, 2020. [ Journal Article ]

Dual Roles of Poly(dA:dT) Tracts in Replication Initiation and Fork Collapse

Tubbs A, Sridharan S, van Wietmarschen N, Maman Y, Callen E, Stanlie A, Wu W, Wu X, Day A, Wong N, Yin M, Canela A, Fu H, Redon C, Pruitt SC, Jaszczyszyn Y, Aladjem MI, Aplan PD, Hyrien O, Nussenzweig A

Cell. 174(5) : 1127-1142, 2018. [ Journal Article ]

Biography

Chief

Andre Nussenzweig, Ph.D.

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, a National Institutes of Health Distinguished Investigator and a 2019 inductee into the US National Academy of Medicine. In 2023, Dr. Nussenzweig was inducted into the American Academy of Arts and Sciences as well as the National Academy of Sciences.