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

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

Nature communications (2023-12-19)
Aldo S Bader, Martin Bushell
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
KU-55933, ≥98% (HPLC)
Sigma-Aldrich
VE-821, ≥98% (HPLC)