Agnel Sfeir, PhD
Assistant Professor of Cell Biology
Ph.D., 2006, The University of Texas Southwestern Medical Center
Stem Cell Biology, Chromosome biology, Telomere length regulation, DNA damage signaling and repair.
Embryonic Stem Cells, Telomeres, Telomerase, DNA damage and repair, iPS
Skirball Institute of Biomolecular Medicine
Developmental Genetics Program
New York University School of Medicine
540 First Ave. 4th floor
New York, NY 10016
In normal human somatic cells, telomeres progressively shorten with ongoing cellular divisions due to the inability of the DNA replication machinery to copy each chromosome until the very end. When a subset of telomeres within a cell becomes short, a DNA damage signal is triggered to activate the p53 and Rb pathways that ultimately induce cellular senescence. This is known as the Hayflick limit and is the basis of the tumor suppressive function of telomere shortening.
Cells that accumulate mutations in the checkpoint pathways are capable of bypassing this stage and proliferate further, resulting in additional telomere shortening. This is followed by complete telomere erosion, which engages DNA repair machineries, leading to a stage of extensive chromosome instability, known as crisis. Very few cells can bypass both senescence and crisis and they do so by upregulating telomere maintenance pathways, which either involve activating telomerase or inducing telomere recombination. These cells are then able to progress and become the increasingly aggressive tumors. This scenario highlights the importance of fully understanding telomere maintenance and homeostasis in mammalian cells, which is the focus of our lab.
Telomere lengthening 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. To do so, we rely on iPSc (induced pluripotent stem cell) induction with four transcription factors (Oct4, Sox2, c-Myc and Klf4) as a reprogramming platform to decipher telomere resetting. We also follow several non-biased approaches to identify novel genes that control the extent of telomere elongation and telomerase activity during the reprogramming process.
Telomere dynamics in cancer biology:
Telomere dysfunction is a major source of genomic instability that fuels cancer progression. Telomere function is lost when the repetitive sequence becomes too short or when the shelterin complex that binds to the DNA is lacking. A second area of interest to us is to understand how does telomere dysfunction impact cellular function leading to tumorigenesis. While normal human somatic cells lack the activity of the enzyme, telomerase is active in stem cells, progenitor cells of self-renewing tissues, reproductive cells and the majority of cancer cells. Being an obligate means for the indefinite growth of cancer cells, telomerase constitutes a very promising target for cancer therapy and understanding the details of its action is key to allow it to be further explored in cancer therapy.
- Yeung F, Mateos-Gomez PM, Pinzaru A, Ceccarini G, Kabir S, Fernández-Hernando C, and Sfeir A (2013). Non-telomeric role for Rap1 in regulating metabolism and protecting against obesity. Cell Reports. Jun 27;3(6):1847-56. PMID: 23791522
- Sfeir A(2012). Telomeres at a glance. Journal of Cell Science. Sep 15; 125 (pt18):4173-4178. PMID: 23135002
- Sfeir A and de Lange T (2012). Removal of shelterin reveals the telomere end-protection problem. Science. May 4; 336 (6081):593-597. PMID: 22556254
- Scherthan H, Sfeir A and de Lange T (2011). Rap1-independent telomere attachment and bouquet formation in mammalian meiosis. Chromosoma. Apr;120(2):151-7. PMID: 20927532
- Kabir S, Sfeir A and de Lange T (2010). Taking apart Rap1; An adaptor protein with telomeric and non-telomeric functions. Cell Cycle. Oct 15;9(20):4061-7. PMID: 20948311
- Sfeir A,Kabir S, van Overbeek M, Celli G, and de Lange T (2010). Loss of Rap1 induces telomere recombination in absence of NHEJ or a DNA damage signal. Science. Mar 26;327(5973):1657-61. PMID: 20339076
- Zhao Y, Sfeir AJ, Zou Y, Buseman CM, Chow TT, Shay JW, Wright WE (2009). Telomere extension occurs at most chromosome ends and is uncoupled from fill-in in human cancer cells. Cell. Aug 7;138(3):463-75. PMID: 19665970
- Sfeir A, Settapong K, Hockemeyer D, McRae SL, Karlseder J, Schildkraut K, and de Lange T (2009). Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication. Cell. Jul 10;138(1):90-103 (Cover). PMID: 19596237