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Neurological Cockayne Syndrome Results from R-Loops Induced by Stalled RNA Polymerase II during Transcription Elongation

ABSTRACT: Mutations in the Cockayne Syndrome group B (CSB) gene cause severe neurodevelopmental defects and premature aging. As a member of the SWI/SNF family of chromatin remodelers, CSB is best known for its role in transcription-coupled nucleotide excision (TC-NER), but this function neither explains the major disease phenotype nor offers any clue about the selective vulnerability in neurons. Pursuing Cockayne Syndrome-associated genome instability, we uncover an intrinsic mechanism by which elongating RNA polymerase II (RNAPII) undergoes transient pausing at internal T-runs where CSB is required to push RNAPII forward. Consequently, CSB deficiency retards RNAPII elongation in these regions, and when coupled upstream G-rich sequences, such functional defects are further amplified to induce genome instability via augmented R-loop formation. As such R-loop prone motifs are proportionally represented in long genes that predominately function in neurons, this mechanism provides critical insights into selective neuronal vulnerability. Moreover, because of divergent intronic sequences between mice and humans, this mechanism also explains why mice deficient for CSB do not develop severe neurological abnormalities as seen in humans, suggesting that the manifestation of Cockayne Syndrome phenotype results from progressive genome evolution in mammals.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE226204 | GEO | 2024/07/29

REPOSITORIES: GEO

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Project description:Cockayne syndrome is an inherited premature aging syndrome associated with developmental and neurological disorders. Mutations in the genomic locus encoding CSB are associated with 80% Cockayne syndrome cases. Transcription profiling assays reveal the association of mis-regulation of gene expression with Cockayne syndrome, highlighting the importance of CSB in transcription regulation. However, many questions remain unanswered as how CSB regulates transcription. In this study, we dissect the mechanisms by which CSB regulates transcription during normal growth. By anti-CSB chromatin immunoprecipitation followed by deep sequencing, we found CSB is enriched at genomic regions containing TGASTCA motifs, to which the immediate early gene product C-Jun binds specifically. We further demonstrate that c-Jun co-immunoprecipitates with CSB. In addition, the targeting of CSB to genomic region containing TGASTCA motifs was drastically reduced in cells treated c-Jun shRNA. Reverse transcription followed by quantitative PCR indicates that CSB can regulate gene expression nearby its binding sites, both in activation and repression. The remodeling defective CSBM-bM-^HM-^FN1 mutant is also targeted to TGASTCA motifs, but cannot always substitute CSB function in transcription regulating, suggesting the importance of remodeling by CSB in transcription regulation. Notably, the Cockayne syndrome related mutation encoding protein CSBR670W, which is defective in ATP hydrolysis but is targeted to TGASTCA motifs efficiently, indicating that ATP hydrolysis is dispensable for c-Jun mediated CSB targeting, in sharp contrast to the ATP-dependent targeting mechanism by which CSB is relocated to DNA lesion stalled transcription. Together, these results reveal a second CSB targeting mechanism in which DNA sequence specific transcription factor c-Jun targets CSB to specific genomic region and regulate gene expression. Genomic localization of CSB and remodeling deficient CSBM-bM-^HM-^FN1

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Neurological Cockayne Syndrome Results from R-Loops Induced by Stalled RNA Polymerase II during Transcription Elongation

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