Chromothripsis during telomere crisis is independent of NHEJ, and consistent with a replicative origin

Kez Cleal, Rhiannon E. Jones, Julia W. Grimstead, Eric A. Hendrickson, Duncan M. Baird

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Telomere erosion, dysfunction, and fusion can lead to a state of cellular crisis characterized by large-scale genome instability. We investigated the impact of a telomere-driven crisis on the structural integrity of the genome by undertaking whole-genome sequence analyses of clonal populations of cells that had escaped crisis. Quantification of large-scale structural variants revealed patterns of rearrangement consistent with chromothripsis but formed in the absence of functional nonhomologous end-joining pathways. Rearrangements frequently consisted of short fragments with complex mutational patterns, with a repair topology that deviated from randomness showing preferential repair to local regions or exchange between specific loci. We find evidence of telomere involvement with an enrichment of fold-back inversions demarcating clusters of rearrangements. Our data suggest that chromothriptic rearrangements caused by a telomere crisis arise via a replicative repair process involving template switching.

Original languageEnglish (US)
Pages (from-to)737-749
Number of pages13
JournalGenome research
Volume29
Issue number5
DOIs
StatePublished - May 2019

Bibliographical note

Funding Information:
The Baird laboratory was supported by Cancer Research UK (C17199/A18246). The Hendrickson laboratory was supported by grants from the National Cancer Institute (CA154461) and National Institutes of Health General Medical Sciences (GM088351).

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