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CDK12 controls transcription at damaged genes and prevents MYC-induced transcription-replication conflicts

2024; Nature Portfolio; Volume: 15; Issue: 1 Linguagem: Inglês

10.1038/s41467-024-51229-5

2041-1723

Laura Curti, Sara Rohban, Nicola Bianchi, Ottavio Croci, Adrian Andronache, Sara Barozzi, Michela Mattioli, Fernanda Ricci, Elena Pastori, Silvia Sberna, Simone Bellotti, Anna Accialini, Roberto Ballarino, Nicola Crosetto, Mark Wade, Dario Parazzoli, Stefano Campaner,

Genomics and Chromatin Dynamics

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.