Assistant Professor, Skirball Institute of Biomolecular Medicine, Developmental Genetics. Department of Cell Biology
Ph.D., 2006 University of Texas Southwestern Medical Center
Telomere, Telomerase, Chromosomes, Genome stability, mtDNA
Skirball Institute of Biomolecular Medicine
540 First Avenue 4th floor, Lab 3
New York, N.Y. 10016
Office Tel: (646) 501-6742
Lab Tel: (646) 501-6743
Fax: (212) 263-7760
Tel: (646) 501-0679
Telomere maintenance in mammalian cells
Chromosomes are the fundamental structural units of our genome. Understanding their basic biology and how their mismanagement leads to disease is the main focus of the Sfeir lab. The scientific questions we address cover three major areas of research:
1- Telomere regulation during embryonic development
Appropriate telomere length is critical for survival of cells. Despite telomere length variations amongst different species, telomeres are maintained within a set range for any given species. One of the main goals of our lab is to understand the mechanisms underlying telomere length regulation. In particularly, we are interested in uncovering the pathways that reset telomere length during embryonic development, a process that is recapitulated during nuclear reprogramming.
2- Telomere dysfunction, DNA repair, and cancer
In recent years, a robust and very error-prone repair pathway termed Alternative-NHEJ (alt-NHEJ) emerged as a novel, yet largely uncharacterized, repair machinery that covalently fuses broken DNA ends. Alt-NHEJ is the primary mediator of non-reciprocal chromosomal translocation and appears to be a major repair pathway that acts at dysfunctional telomeres. The factors that mediate alt-NHEJ remain unknown, yet recent work including ours, has highlighted certain candidates: Polymerase theta, Lig3, PARP1, and CtIP. Our goal in the lab is to uncover the full spectrum of genes that promote this repair pathway, and study their effect on the development and progression of both sporadic and inherited breast cancers.
3- Investigating mtDNA replication and repair
Acquired genomic aberrations in mtDNA lead to mitochondrial dysfunction, a chief cause of neurological and aging diseases. mtDNA mutations, ranging from single-base substitutions to large-scale deletions, are also found in high frequency in many tumors, and recent experiments have established their role in driving metastasis. Among the different mutations, large- scale deletions are especially dangerous owing to their smaller size, which allows them to propagate faster and overtake the mitochondrial genome. While the underlying basis for mtDNA deletions is unknown, two scenarios can explain their formation – infidelity of DNA replication machinery or errors in DNA double-strand break (DSB) repair. A major goal in the lab is to elucidate the molecular mechanism of mtDNA instability by deciphering both facets of mtDNA metabolism – replication and repair – and test if their deregulation causes deletions in the mitochondrial genome.
Sfeir, A, Symington, L. (2015) Microhomology-Mediated End Joining: A Back-up Survival Mechanism or Dedicated Pathway? Trends Biochem Sci. Sep 21. pii: S0968-0004(15)00158-9.
Mateos-Gomez PA, Gong F, Nair N, Miller KM, Lazzerini-Denchi E, Sfeir A. (2014) Mammalian Polymerase Theta Promotes Alternative-NHEJ and Suppresses Recombination. Nature. Feb 12;518(7538):254-7. PMID: 25642960
- Yeung F, Mateos-Gomez P, Pinzaru A, Ceccarini G, Kabir S, and Sfeir A. (2013) Non-telomeric role for RAP1 in regulating metabolism and protecting against obesity. Cell Reports. S2211-1247(13)00249-0. PMID: 23791522
- Sfeir, Agnel and de Lange, Titia. Removal of shelterin reveals the telomere end-protection problem. 2012 May 4; 336 (6081):593-597 Science. PMID: 22556254
- Sfeir, Agnel; Kosiyatrakul, Settapong T; Hockemeyer, Dirk; MacRae, Sheila L; Karlseder, Jan; Schildkraut, Carl L; de Lange, Titia. Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication. 2009 Jul 10;138(1):90-103, Cell. PMID: 19596237