Article
MDC1 maintains active elongation complexes of RNA polymerase II
Author/s | Pappas, George
Munk, Sebastian Howen Nesgaard Watanabe, Kenji Thomas, Quentin Gal, Zita Gram, Helena Hagner Lee, MyungHee Gómez Cabello, Daniel Bartek, Jiri |
Department | Universidad de Sevilla. Departamento de Biología Celular |
Publication Date | 2023 |
Deposit Date | 2023-02-10 |
Published in |
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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 ... 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. |
Funding agencies | European Union (UE) Danish Cancer Society. Denmark Lundbeck Foundation Novo Nordisk Foundation Swedish Research Council Danish Council for Independent Research. Denmark Japan Society for the Promotion of Science (JSPS) Independent Research Fund Denmark |
Project ID. | 722729
R167-A11068 R204-A12617-B153 R311-A18224 R266-2017-4289 VR-MH 2014-46602-117891-30 DFF-7016-00313 JP19K23927 JP20K07578 NNF20OC0060590 NNF18OC0052647 NNF20OC0059959 0165-00092B 8045-00057A |
Citation | Pappas, G., Munk, S.H.N., Watanabe, K., Thomas, Q., Gal, Z., Gram, H.H.,...,Bartek, J. (2023). MDC1 maintains active elongation complexes of RNA polymerase II. Cell Reports, 42 (1), 111979. https://doi.org/10.1016/j.celrep.2022.111979. |
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