Professor Eric Hendrickson

Biochem,Molec Biol,Biophy MEDX
Medical School
Twin Cities
Project Title: 
DNA Repair

Telomeres shorten with each cell division and can ultimately become substrates for non-homologous end-joining repair, leading to large-scale genomic rearrangements of the kind frequently observed in human cancers. These researchers have characterised over 1,400 telomere fusion events at the single-molecule level, using a combination of high-throughput sequence analysis together with experimentally-induced telomeric double-stranded DNA breaks. They have found that a single chromosome dysfunctional telomere can fuse with diverse non-telomeric genomic loci, even in the presence of an otherwise stable genome, and that fusion predominates in coding regions. Fusion frequency was markedly increased in the absence of TP53 checkpoint control and significantly modulated by the cellular capacity for classical, versus alternative, non-homologous end joining (NHEJ). The researchers observed a striking reduction in inter-chromosomal fusion events in cells lacking DNA ligase 4, in contrast to a remarkably consistent profile of intra-chromosomal fusion in the context of multiple genetic knockouts, including DNA ligase 3 and 4 double-knockouts. They found distinct mutational signatures associated with classical NHEJ-mediated inter-chromosomal, as opposed to alternative NHEJ-mediated intra-chromosomal telomere fusions and evidence an unanticipated sufficiency of DNA ligase 1 for these intra-chromosomal events. These findings have implications for mechanisms driving cancer genome evolution.

Project Investigators

Professor Eric Hendrickson
Kevin Lin
Brian Ruis
Dr. Nuri Temiz
Chen Wang
 
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