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

J. A. Kamp, R. Schendel, I. W. Dilweg and M. Tijsterman ()
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J. A. Kamp: Leiden University Medical Center
R. Schendel: Leiden University Medical Center
I. W. Dilweg: Leiden University Medical Center
M. Tijsterman: Leiden University Medical Center

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17455-3

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