Multi-step processing of replication stress-derived nascent strand DNA gaps by MRE11 and EXO1 nucleases.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
07 10 2023
07 10 2023
Historique:
received:
02
03
2023
accepted:
27
09
2023
medline:
23
10
2023
pubmed:
8
10
2023
entrez:
7
10
2023
Statut:
epublish
Résumé
Accumulation of single stranded DNA (ssDNA) gaps in the nascent strand during DNA replication has been associated with cytotoxicity and hypersensitivity to genotoxic stress, particularly upon inactivation of the BRCA tumor suppressor pathway. However, how ssDNA gaps contribute to genotoxicity is not well understood. Here, we describe a multi-step nucleolytic processing of replication stress-induced ssDNA gaps which converts them into cytotoxic double stranded DNA breaks (DSBs). We show that ssDNA gaps are extended bidirectionally by MRE11 in the 3'-5' direction and by EXO1 in the 5'-3' direction, in a process which is suppressed by the BRCA pathway. Subsequently, the parental strand at the ssDNA gap is cleaved by the MRE11 endonuclease generating a double strand break. We also show that exposure to bisphenol A (BPA) and diethylhexyl phthalate (DEHP), which are widespread environmental contaminants due to their use in plastics manufacturing, causes nascent strand ssDNA gaps during replication. These gaps are processed through the same mechanism described above to generate DSBs. Our work sheds light on both the relevance of ssDNA gaps as major determinants of genomic instability, as well as the mechanism through which they are processed to generate genomic instability and cytotoxicity.
Identifiants
pubmed: 37805499
doi: 10.1038/s41467-023-42011-0
pii: 10.1038/s41467-023-42011-0
pmc: PMC10560291
doi:
Substances chimiques
Exodeoxyribonucleases
EC 3.1.-
Endonucleases
EC 3.1.-
DNA
9007-49-2
DNA, Single-Stranded
0
EXO1 protein, human
EC 3.1.-
DNA Repair Enzymes
EC 6.5.1.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
6265Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM134681
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES026184
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA244417
Pays : United States
Informations de copyright
© 2023. Springer Nature Limited.
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