Aug 5, 2019

APOBEC3B-dependent kataegis and TREX1-driven chromothripsis in telomere crisis

BioRxiv : the Preprint Server for Biology
John MaciejowskiPeter J Campbell

Abstract

Telomere crisis occurs during tumorigenesis when depletion of the telomere reserve generates unstable dicentric chromosomes. In vitro, telomere crisis instigates chromothripsis and kataegis. As the cytoplasmic nuclease TREX1 contributes to the resolution of dicentric chromosomes, we tested whether TREX1 promotes telomere crisis-associated chromothripsis. Consistent with TREX1- mediated DNA fragmentation, telomere crisis in absence of TREX1 resulted in diminished chromothripsis and increased signatures of Breakage-Fusion-Bridge cycles and other simple rearrangements. In addition to TREX1, APOBEC3B cytosine deamination contributed to telomere crisis-induced genetic alterations. APOBEC3B was required for kataegis at chromothriptic breakpoints and also increases the level of chromothriptic fragmentation, consistent with strand breakage after cytosine deamination. These results establish that chromothripsis and kataegis induced by telomere crisis involves both nucleolytic processing by TREX1 and cytosine editing by APOBEC3B.

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Mentioned in this Paper

DNA Fragmentation
Cytosine
Chromosome Breakage
Chromothripsis
TREX1 gene
TREX1
Telomere
APOBEC3B gene
Carcinogenesis
Cytoplasm

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