Brief Research Summary:

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 length resetting 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 particular, 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. 

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.