BRCA1-associated structural variations are a consequence of polymerase theta-mediated end-joining.

Nature Communications
J A KampMarcel Tijsterman

Abstract

Failure to preserve the integrity of the genome is a hallmark of cancer. Recent studies have revealed that loss of the capacity to repair DNA breaks via homologous recombination (HR) results in a mutational profile termed BRCAness. The enzymatic activity that repairs HR substrates in BRCA-deficient conditions to produce this profile is currently unknown. We here show that the mutational landscape of BRCA1 deficiency in C. elegans closely resembles that of BRCA1-deficient tumours. We identify polymerase theta-mediated end-joining (TMEJ) to be responsible: knocking out polq-1 suppresses the accumulation of deletions and tandem duplications in brc-1 and brd-1 animals. We find no additional back-up repair in HR and TMEJ compromised animals; non-homologous end-joining does not affect BRCAness. The notion that TMEJ acts as an alternative to HR, promoting the genome alteration of HR-deficient cells, supports the idea that polymerase theta is a promising therapeutic target for HR-deficient tumours.

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Citations

Jan 22, 2021·Current Opinion in Genetics & Development·Jeremy SettonSimon N Powell
Mar 11, 2021·Cell Reports·Gurushankar ChandramoulyRichard T Pomerantz
Apr 4, 2021·Cancers·James A Shapiro
May 18, 2021·Frontiers in Cell and Developmental Biology·Qianyan Li, JoAnne Engebrecht
Jun 30, 2021·Current Opinion in Genetics & Development·Ondrej BelanSimon J Boulton
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Jul 27, 2021·DNA Repair·Amr M Al-Zain, Lorraine S Symington
Jul 29, 2021·Nature Reviews. Cancer·Gene KohSerena Nik-Zainal
Aug 12, 2021·Nature Communications·Joost SchimmelMarcel Tijsterman
Aug 31, 2021·Frontiers in Cell and Developmental Biology·Mélanie K ProdhommeAgnès Tissier

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Methods Mentioned

BETA
transgenic

Software Mentioned

Illumina
SAMtools
HRDetect
BWA
TMEJ

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