Similar Datasets
Project description: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.
| S-EPMC11330984 | biostudies-literature
Project description:In order to identify genes and pathways necessary to preserve genome integrity upon Myc over-expression, we conducted a large siRNA-based screen in isogenic lines. We discovered several genes that suppressed the Myc-induced DNA-damage response and that were essential for the cell survival upon Myc activation. We idntified CDK12, a cyclin dependent kinase involved in transcriptional control and genome stability. We uncovered a novel and unexpected role of CDK12 in controlling transcription at loci proximal to DNA damaged sites and dissected its upstream regulatory pathways and downstream effectors. Mechanistic studies and genome-wide mapping of replication dynamics and DSBs revealed how CDK12 is essential to suppress intrinsic transcription-replication conflicts, thus avoiding cytotoxic DNA damage in cancer cells. Overall, this study uncovers a novel role for CDK12 and a new liability of Myc-driven cancers, which could be exploited for therapeutic purposes.
2024-06-19 | GSE236547 | GEO
Project description:In order to identify genes and pathways necessary to preserve genome integrity upon Myc over-expression, we conducted a large siRNA-based screen in isogenic lines. We discovered several genes that suppressed the Myc-induced DNA-damage response and that were essential for the cell survival upon Myc activation. We idntified CDK12, a cyclin dependent kinase involved in transcriptional control and genome stability. We uncovered a novel and unexpected role of CDK12 in controlling transcription at loci proximal to DNA damaged sites and dissected its upstream regulatory pathways and downstream effectors. Mechanistic studies and genome-wide mapping of replication dynamics and DSBs revealed how CDK12 is essential to suppress intrinsic transcription-replication conflicts, thus avoiding cytotoxic DNA damage in cancer cells. Overall, this study uncovers a novel role for CDK12 and a new liability of Myc-driven cancers, which could be exploited for therapeutic purposes.
2024-06-19 | GSE236550 | GEO
Project description:In order to identify genes and pathways necessary to preserve genome integrity upon Myc over-expression, we conducted a large siRNA-based screen in isogenic lines. We discovered several genes that suppressed the Myc-induced DNA-damage response and that were essential for the cell survival upon Myc activation. We idntified CDK12, a cyclin dependent kinase involved in transcriptional control and genome stability. We uncovered a novel and unexpected role of CDK12 in controlling transcription at loci proximal to DNA damaged sites and dissected its upstream regulatory pathways and downstream effectors. Mechanistic studies and genome-wide mapping of replication dynamics and DSBs revealed how CDK12 is essential to suppress intrinsic transcription-replication conflicts, thus avoiding cytotoxic DNA damage in cancer cells. Overall, this study uncovers a novel role for CDK12 and a new liability of Myc-driven cancers, which could be exploited for therapeutic purposes.
2024-06-19 | GSE236549 | GEO
Project description:In order to identify genes and pathways necessary to preserve genome integrity upon Myc over-expression, we conducted a large siRNA-based screen in isogenic lines. We discovered several genes that suppressed the Myc-induced DNA-damage response and that were essential for the cell survival upon Myc activation. We idntified CDK12, a cyclin dependent kinase involved in transcriptional control and genome stability. We uncovered a novel and unexpected role of CDK12 in controlling transcription at loci proximal to DNA damaged sites and dissected its upstream regulatory pathways and downstream effectors. Mechanistic studies and genome-wide mapping of replication dynamics and DSBs revealed how CDK12 is essential to suppress intrinsic transcription-replication conflicts, thus avoiding cytotoxic DNA damage in cancer cells. Overall, this study uncovers a novel role for CDK12 and a new liability of Myc-driven cancers, which could be exploited for therapeutic purposes.
2024-06-19 | GSE236545 | GEO
Project description:In order to identify genes and pathways necessary to preserve genome integrity upon Myc over-expression, we conducted a large siRNA-based screen in isogenic lines. We discovered several genes that suppressed the Myc-induced DNA-damage response and that were essential for the cell survival upon Myc activation. We idntified CDK12, a cyclin dependent kinase involved in transcriptional control and genome stability. We uncovered a novel and unexpected role of CDK12 in controlling transcription at loci proximal to DNA damaged sites and dissected its upstream regulatory pathways and downstream effectors. Mechanistic studies and genome-wide mapping of replication dynamics and DSBs revealed how CDK12 is essential to suppress intrinsic transcription-replication conflicts, thus avoiding cytotoxic DNA damage in cancer cells. Overall, this study uncovers a novel role for CDK12 and a new liability of Myc-driven cancers, which could be exploited for therapeutic purposes.
2024-06-19 | GSE236546 | GEO
Project description:CDK12 prevents MYC-induced transcription-replication conflicts
| PRJNA991561 | ENA
Project description:CDK12 prevents MYC-induced transcription-replication conflicts [BLISS]
| PRJNA991555 | ENA
Project description:CDK12 prevents MYC-induced transcription-replication conflicts [EdU-seq]
| PRJNA991567 | ENA
Project description:CDK12 prevents MYC-induced transcription-replication conflicts [ChIP-seq]
| PRJNA991553 | ENA