MDC1 maintains active elongation complexes of RNA polymerase II
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MDC1 maintains active elongation complexes of RNA polymerase II. / Pappas, George; Munk, Sebastian Howen Nesgaard; Watanabe, Kenji; Thomas, Quentin; Gál, Zita; Gram, Helena Hagner; Lee, Myung Hee; Gómez-Cabello, Daniel; Kanellis, Dimitris Christos; Olivares-Chauvet, Pedro; Larsen, Dorthe Helena; Gregersen, Lea Haarup; Maya-Mendoza, Apolinar; Galanos, Panagiotis; Bartek, Jiri.
I: Cell Reports, Bind 42, Nr. 1, 111979, 2023.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - MDC1 maintains active elongation complexes of RNA polymerase II
AU - Pappas, George
AU - Munk, Sebastian Howen Nesgaard
AU - Watanabe, Kenji
AU - Thomas, Quentin
AU - Gál, Zita
AU - Gram, Helena Hagner
AU - Lee, Myung Hee
AU - Gómez-Cabello, Daniel
AU - Kanellis, Dimitris Christos
AU - Olivares-Chauvet, Pedro
AU - Larsen, Dorthe Helena
AU - Gregersen, Lea Haarup
AU - Maya-Mendoza, Apolinar
AU - Galanos, Panagiotis
AU - Bartek, Jiri
N1 - Publisher Copyright: © 2023 The Authors
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - cancer
KW - CP: Molecular biology
KW - DNA double-strand breaks
KW - MDC1
KW - pre-mRNA splicing
KW - RNA polymerase II
KW - transcription elongation
U2 - 10.1016/j.celrep.2022.111979
DO - 10.1016/j.celrep.2022.111979
M3 - Journal article
C2 - 36640322
AN - SCOPUS:85147106239
VL - 42
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 1
M1 - 111979
ER -
ID: 336769794