Sister chromatid telomere fusions, but not NHEJ-mediated inter-chromosomal telomere fusions, occur independently of DNA ligases 3 and 4

摘要: Telomeres shorten with each cell division and can ultimately become substrates for nonhomologous end-joining repair, leading to large-scale genomic rearrangements of the kind frequently observed in human cancers. We have characterized more than 1400 telomere fusion events at single-molecule level, using a combination high-throughput sequence analysis together experimentally induced telomeric double-stranded DNA breaks. show that single chromosomal dysfunctional fuse diverse nontelomeric loci, even presence an otherwise stable genome, predominates coding regions. Fusion frequency was markedly increased absence TP53 checkpoint control significantly modulated by cellular capacity classical, versus alternative, end joining (NHEJ). striking reduction inter-chromosomal cells lacking ligase 4, contrast remarkably consistent profile intra-chromosomal context multiple genetic knockouts, including 3 4 double-knockouts. reveal distinct mutational signatures associated classical NHEJ-mediated inter-chromosomal, as opposed alternative intra-chromosomal, fusions evidence unanticipated sufficiency 1 these events. Our findings implications mechanisms driving cancer genome evolution.