1. MDC1 maintains active elongation complexes of RNA polymerase II
- Author
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George Pappas, Sebastian Howen Nesgaard Munk, Kenji Watanabe, Quentin Thomas, Zita Gál, Helena Hagner Gram, MyungHee Lee, Daniel Gómez-Cabello, Dimitris Christos Kanellis, Pedro Olivares-Chauvet, Dorthe Helena Larsen, Lea Haarup Gregersen, Apolinar Maya-Mendoza, Panagiotis Galanos, and Jiri Bartek
- Subjects
Molecular biology [CP] ,Cancer Research ,pre-mRNA splicing ,cancer ,DNA double-strand breaks ,MDC1 ,RNA polymerase II ,transcription elongation ,General Biochemistry, Genetics and Molecular Biology - Abstract
The role of MDC1 in the DNA damage response has been extensively studied; however, its impact on other cellular processes is not well understood. Here, we describe the role of MDC1 in transcription as a regulator of RNA polymerase II (RNAPII). Depletion of MDC1 causes a genome-wide reduction in the abundance of actively engaged RNAPII elongation complexes throughout the gene body of protein-encoding genes under unperturbed conditions. Decreased engaged RNAPII subsequently alters the assembly of the spliceosome complex on chromatin, leading to changes in pre-mRNA splicing. Mechanistically, the S/TQ domain of MDC1 modulates RNAPII-mediated transcription. Upon genotoxic stress, MDC1 promotes the abundance of engaged RNAPII complexes at DNA breaks, thereby stimulating nascent transcription at the damaged sites. Of clinical relevance, cancer cells lacking MDC1 display hypersensitivity to RNAPII inhibitors. Overall, we unveil a role of MDC1 in RNAPII-mediated transcription with potential implications for cancer treatment.
- Published
- 2023
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