iMUT-seq: high-resolution DSB-induced mutation profiling reveals prevalent homologous-recombination dependent mutagenesis

Aldo S. Bader () and Martin Bushell ()
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Aldo S. Bader: Cancer Research UK Beatson Institute
Martin Bushell: Cancer Research UK Beatson Institute

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract DNA double-strand breaks (DSBs) are the most mutagenic form of DNA damage, and play a significant role in cancer biology, neurodegeneration and aging. However, studying DSB-induced mutagenesis is limited by our current approaches. Here, we describe iMUT-seq, a technique that profiles DSB-induced mutations at high-sensitivity and single-nucleotide resolution around endogenous DSBs. By depleting or inhibiting 20 DSB-repair factors we define their mutational signatures in detail, revealing insights into the mechanisms of DSB-induced mutagenesis. Notably, we find that homologous-recombination (HR) is more mutagenic than previously thought, inducing prevalent base substitutions and mononucleotide deletions at distance from the break due to DNA-polymerase errors. Simultaneously, HR reduces translocations, suggesting a primary role of HR is specifically the prevention of genomic rearrangements. The results presented here offer fundamental insights into DSB-induced mutagenesis and have significant implications for our understanding of cancer biology and the development of DDR-targeting chemotherapeutics.

Date: 2023
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DOI: 10.1038/s41467-023-44167-1

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