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

Xuan Zhang, Jun Xu, Jing Hu, Sitao Zhang, Yajing Hao, Dongyang Zhang, Hao Qian, Dong Wang () and Xiang-Dong Fu ()
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Xuan Zhang: University of California San Diego
Jun Xu: University of California San Diego
Jing Hu: University of Electronic Science and Technology of China
Sitao Zhang: National Institute of Biological Sciences,7 Science Park Road
Yajing Hao: University of California San Diego
Dongyang Zhang: University of California San Diego
Hao Qian: University of Electronic Science and Technology of China
Dong Wang: University of California San Diego
Xiang-Dong Fu: Westlake University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-50298-w

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