Cockayne Syndrome Linked to Elevated R-Loops Induced by Stalled RNA Polymerase II during Transcription Elongation.

Autor: Zhang X; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.; Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, USA., Xu J; Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.; Genetics and Metabolism Department, The Children's Hospital, School of Medicine, Zhejiang University, National Clinical Research Center for Child Health, Hangzhou, China.; The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, China., Hu J; Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China., Zhang S; National Institute of Biological Sciences,7 Science Park Road, Beijing, China., Hao Y; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.; China National Center for Bioinformation, Beijing, China.; Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.; University of Chinese Academy of Sciences, 100049, Beijing, China., Zhang D; Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, USA., Qian H; Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China., Wang D; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA. dow003@health.ucsd.edu.; Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, USA. dow003@health.ucsd.edu.; Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA. dow003@health.ucsd.edu., Fu XD; Westlake Laboratory of Life Sciences and Biomedicine, School of Life Sciences and School of Medicine, Westlake University, Hangzhou, Zhejiang, China. fuxiangdong@westlake.edu.cn.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jul 17; Vol. 15 (1), pp. 6031. Date of Electronic Publication: 2024 Jul 17.
DOI: 10.1038/s41467-024-50298-w
Abstrakt: Mutations in the Cockayne Syndrome group B (CSB) gene cause cancer in mice, but premature aging and severe neurodevelopmental defects in humans. CSB, a member of the SWI/SNF family of chromatin remodelers, plays diverse roles in regulating gene expression and transcription-coupled nucleotide excision repair (TC-NER); however, these functions do not explain the distinct phenotypic differences observed between CSB-deficient mice and humans. During investigating Cockayne Syndrome-associated genome instability, we uncover an intrinsic mechanism that involves elongating RNA polymerase II (RNAPII) undergoing transient pauses at internal T-runs where CSB is required to propel RNAPII forward. Consequently, CSB deficiency retards RNAPII elongation in these regions, and when coupled with G-rich sequences upstream, exacerbates genome instability by promoting R-loop formation. These R-loop prone motifs are notably abundant in relatively long genes related to neuronal functions in the human genome, but less prevalent in the mouse genome. These findings provide mechanistic insights into differential impacts of CSB deficiency on mice versus humans and suggest that the manifestation of the Cockayne Syndrome phenotype in humans results from the progressive evolution of mammalian genomes.
(© 2024. The Author(s).)
Databáze: MEDLINE
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