Cohesin maintains replication timing to suppress DNA damage on cancer genes.
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
received:
29
09
2022
accepted:
26
06
2023
medline:
11
8
2023
pubmed:
28
7
2023
entrez:
27
7
2023
Statut:
ppublish
Résumé
Cohesin loss-of-function mutations are frequently observed in tumors, but the mechanism underlying its role in tumorigenesis is unclear. Here, we found that depletion of RAD21, a core subunit of cohesin, leads to massive genome-wide DNA breaks and 147 translocation hotspot genes, co-mutated with cohesin in multiple cancers. Increased DNA damages are independent of RAD21-loss-induced transcription alteration and loop anchor disruption. However, damage-induced chromosomal translocations coincide with the asymmetrically distributed Okazaki fragments of DNA replication, suggesting that RAD21 depletion causes replication stresses evidenced by the slower replication speed and increased stalled forks. Mechanistically, approximately 30% of the human genome exhibits an earlier replication timing after RAD21 depletion, caused by the early initiation of >900 extra dormant origins. Correspondingly, most translocation hotspot genes lie in timing-altered regions. Therefore, we conclude that cohesin dysfunction causes replication stresses induced by excessive DNA replication initiation, resulting in gross DNA damages that may promote tumorigenesis.
Identifiants
pubmed: 37500731
doi: 10.1038/s41588-023-01458-z
pii: 10.1038/s41588-023-01458-z
doi:
Substances chimiques
DNA-Binding Proteins
0
Cell Cycle Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1347-1358Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
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