iMUT-seq: high-resolution DSB-induced mutation profiling reveals prevalent homologous-recombination dependent mutagenesis.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
18 Dec 2023
18 Dec 2023
Historique:
received:
01
04
2022
accepted:
04
12
2023
medline:
19
12
2023
pubmed:
19
12
2023
entrez:
18
12
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 38110444
doi: 10.1038/s41467-023-44167-1
pii: 10.1038/s41467-023-44167-1
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
8419Subventions
Organisme : Cancer Research UK (CRUK)
ID : A17196
Organisme : Cancer Research UK (CRUK)
ID : A31287
Organisme : Cancer Research UK (CRUK)
ID : A29252
Organisme : Cancer Research UK (CRUK)
ID : A29252
Organisme : Cancer Research UK (CRUK)
ID : C17918/A28870
Informations de copyright
© 2023. The Author(s).
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