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PMID: 26687355 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Chromothripsis and Kataegis Induced by Telomere Crisis.

Cell ·Vol. 163 ·No. 7 ·2015-12-17 ·Pages 1641-54

Maciejowski J, Li Y, Bosco N, Campbell PJ, de Lange T

Abstract

Telomere crisis occurs during tumorigenesis when depletion of the telomere reserve leads to frequent telomere fusions. The resulting dicentric chromosomes have been proposed to drive genome instability. Here, we examine the fate of dicentric human chromosomes in telomere crisis. We observed that dicentric chromosomes invariably persisted through mitosis and developed into 50-200 μm chromatin bridges connecting the daughter cells. Before their resolution at 3-20 hr after anaphase, the chromatin bridges induced nuclear envelope rupture in interphase, accumulated the cytoplasmic 3' nuclease TREX1, and developed RPA-coated single stranded (ss) DNA. CRISPR knockouts showed that TREX1 contributed to the generation of the ssDNA and the resolution of the chromatin bridges. Post-crisis clones showed chromothripsis and kataegis, presumably resulting from DNA repair and APOBEC editing of the fragmented chromatin bridge DNA. We propose that chromothripsis in human cancer may arise through TREX1-mediated fragmentation of dicentric chromosomes formed in telomere crisis.

Keywords
APOBEC NERDI TREX1 chromothripsis dicentric chromosome kataegis telomere crisis
MeSH Terms
Chromosomal Instability Chromosome Aberrations Chromosomes, Human Cytokinesis DNA, Single-Stranded/metabolism Exodeoxyribonucleases/metabolism Genomic Instability Humans Mitosis Neoplasms/genetics Nuclear Envelope/metabolism Phosphoproteins/metabolism Telomere
Chemicals
DNA, Single-Stranded Phosphoproteins Exodeoxyribonucleases three prime repair exonuclease 1
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Maciejowski John
Laboratory for Cell Biology and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Li Yilong
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton Cambridge, CB10 1SA, UK.
Bosco Nazario
Laboratory for Cell Biology and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Campbell Peter J
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton Cambridge, CB10 1SA, UK. Electronic address: pc8@sanger.ac.uk.
de Lange Titia
Laboratory for Cell Biology and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. Electronic address: delange@mail.rockefeller.edu.
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2015.11.054
Email
pc8@sanger.ac.uk
delange@mail.rockefeller.edu
Published
2015-12-17
Pages
1641-54
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC4687025
Subset
IM
Grants
Wellcome Trust · WT088340MA · United Kingdom
Wellcome Trust · 077012/Z/05/Z · United Kingdom
NCI NIH HHS · 5R01CA181090 · United States
NCI NIH HHS · R01 CA181090 · United States
NCI NIH HHS · P30 CA008748 · United States
Wellcome Trust · 103858 · United Kingdom
External Links
PubMed source DOI: 10.1016/j.cell.2015.11.054 PMC Full Text View journal details
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