Skirball Institute / Department of Cell Biology
New York University School of Medicine
Our research focuses on genome instability. Specifically, we are interested in characterizing error-prone repair pathways employed by cancer cells.
Our ultimate goal is to develop novel and more effective therapies for breast and ovarian cancer. Our innovative work is providing fundamental insights into questions related to DNA repair pathways that augment genomic instability in cancer cells.
Agnel Sfeir received her B.S. and M.Sc. in Biology from the American University of Beirut. She then moved to the United States to pursue her Ph.D. in Cell Biology in the laboratory of Jerry Shay and Woodring Wright at the University of Texas Southwestern Medical Center. After completing her post-doctoral training with Titia de Lange at the Rockefeller University, she joined the Skirball Institute at NYU Langone Medical Center as an assistant professor in January of 2012. Her research focuses on how mammalian cells ensure the stability of their genomes and avoid becoming tumorigenic. She is the recipient of numerous awards, including the NIH Director’s New Innovator Award, Pew-Stewart Scholarship for Cancer Research, Damon Runyon-Rachleff Innovator Award, V-Foundation Scholar Award, Breast Cancer Alliance Award, V-foundation Award, Human Frontier Science Program Young Investigator Award, and an award from The David and Lucile Packard Foundation.
Investigating Error-Prone DNA Repair in Cancer
Our genome witnesses thousands of lesions on a daily basis, and DNA double-strand breaks (DSBs) are the most cytotoxic insults with immense mutagenic potential. Mistakes made during DSB repair can corrupt our genetic information and result in chromosomal deletions, translocations and rearrangements. Cells have evolved special ways to repair DSBs and thus avoid errors in gene expression.
“I am honored to be part of this esteemed group of early-stage investigators who are working towards understanding the basis of cancer. With support from the Pershing Square Sohn Prize, my lab and I will pursue risky approaches to identify all molecular players in cancer and highlight novel ways to treat this disease.”
There are three distinct pathways to repair a DSB in mammalian cells. The preferred pathway is that of homologous recombination (HR), which fixes DNA breaks without altering the original DNA sequence. The two other pathways are classical Non-Homologous End-Joining (NHEJ) and alternative NHEJ (alt-NHEJ) pathways, the latter being most error-prone. In recent years it has become evident that alt-NHEJ promotes chromosomal translocations, acts at chromosomes ends when they become uncapped, and competes with HR to process breaks that naturally accumulate during genome duplication. Such genome destabilizing events are linked to the initiation, progression, and drug resistance of cancers. Recent evidences suggest that certain types of cancers are genetically predisposed to use the dangerous alt-NHEJ pathway. Our goal is to identify the molecular players and uncover the mechanistic basis of this error-prone DSB repair pathway. We also plan to exploit alt-NHEJ inhibition in cancer therapy.
”Innovation is key to groundbreaking research. It involves applying new and unconventional approaches to tackle difficult biological questions.“