CDK12 controls transcription at damaged genes and prevents MYC-induced transcription-replication conflicts.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
18 Aug 2024
18 Aug 2024
Historique:
received:
15
11
2023
accepted:
01
08
2024
medline:
19
8
2024
pubmed:
19
8
2024
entrez:
18
8
2024
Statut:
epublish
Résumé
The identification of genes involved in replicative stress is key to understanding cancer evolution and to identify therapeutic targets. Here, we show that CDK12 prevents transcription-replication conflicts (TRCs) and the activation of cytotoxic replicative stress upon deregulation of the MYC oncogene. CDK12 was recruited at damaged genes by PARP-dependent DDR-signaling and elongation-competent RNAPII, to repress transcription. Either loss or chemical inhibition of CDK12 led to DDR-resistant transcription of damaged genes. Loss of CDK12 exacerbated TRCs in MYC-overexpressing cells and led to the accumulation of double-strand DNA breaks, occurring between co-directional early-replicating regions and transcribed genes. Overall, our data demonstrate that CDK12 protects genome integrity by repressing transcription of damaged genes, which is required for proper resolution of DSBs at oncogene-induced TRCs. This provides a rationale that explains both how CDK12 deficiency can promote tandem duplications of early-replicated regions during tumor evolution, and how CDK12 targeting can exacerbate replicative-stress in tumors.
Identifiants
pubmed: 39155303
doi: 10.1038/s41467-024-51229-5
pii: 10.1038/s41467-024-51229-5
doi:
Substances chimiques
CDK12 protein, human
EC 2.7.11.22
Cyclin-Dependent Kinases
EC 2.7.11.22
Proto-Oncogene Proteins c-myc
0
RNA Polymerase II
EC 2.7.7.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
7100Subventions
Organisme : Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)
ID : IG-1313
Informations de copyright
© 2024. The Author(s).
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