André Nussenzweig delivered a School of Medicine Basic Sciences Apex Lecture to a full house on Dec. 15. Nussenzweig is chief of the Laboratory of Genome Integrity in the Center for Cancer Research at the National Cancer Institute.
Nussenzweig is a leading contributor to the study of mechanisms that maintain genome stability and prevent cancer. His laboratory discovered how DNA repair pathway selection controls genome integrity and contributes to cancer drug resistance and sensitivity. They have invented technologies that include sequencing strategies to identify locations of DNA strand breaks and generate site-specific DNA damage. These methods reveal intricate mechanisms controlling genome stability in both mitotic and post-mitotic cells.
In his talk, Nussenzweig discussed DNA replication fork dynamics in mammalian cells, particularly stalled replication forks and their repair mechanisms. He explained the use of genome-wide approaches to detect collapsed and stalled replication forks, highlighting the difference between collapsed forks, which result in double-stranded DNA breaks, and stalled forks, which can recover. He showed that forks stall at specific locations in the genome that correspond to actively transcribed genes. He speculated on the causes of this pattern, how it corresponds to the chromosomal abnormalities frequently seen in cancer, and how he plans to decipher the mechanisms.
Nussenzweig also shared the unexpected finding that, contrary to expectations, inactivating DNA repair in post-mitotic neurons promotes neuronal survival. While the chemotherapeutic cisplatin can help treat cancer by binding to and damaging cancer cells’ DNA, thereby stopping their growth and division, it can harm neurons, causing nerve damage. Nussenzweig revealed that disabling a broad DNA repair pathway called nucleotide excision repair, helped neurons survive by conserving scarce nucleotides, DNA building blocks. Boosting nucleotides—through supplementation or by inhibiting the human enzyme that regulates nucleotides, SamHD1 —reduced DNA breaks, suggesting a way to lessen chemotherapy-related nerve damage. He noted that collaboration with other groups is needed to test the hypothesis and identify ways to increase the nucleotide pool in neurons to prevent peripheral neuropathy.
At the end of his talk, Nussenzweig fielded questions from faculty and students.
About the speaker Nussenzweig received his bachelor’s degree in physics from New York University and his doctoral degree in physics from Yale. He pursued his postdoctoral training at the Laboratoire de spectroscopie Hertzienne de l’École normale supérieure in France and the Memorial Sloan Kettering Cancer Center. He started at the National Institutes of Health as a senior investigator in experimental immunology, where he rose up the ranks until he was promoted to branch chief in 2011. He was given the title of “NIH distinguished investigator” in 2016. Nussenzweig is a member of the American Academy of Sciences, the National Academy of Medicine, and the National Academy of Sciences.
He is currently the chief of the Laboratory of Genome Integrity in the Center for Cancer Research at the National Cancer Institute.