Role of Cockayne Syndrome B (CSB) Protein in Genome Maintenance in Human Cells under Oxidative Stress

Abstract

Cockayne Syndrome (CS), a disorder marked by premature ageing and neurodevelopmental abnormalities, is primarily caused by mutations in the CSB protein, a critical component of the transcription-coupled repair pathway of nucleotide excision repair. This study explores the role of CSB in managing oxidative DNA damage and maintaining telomere integrity under oxidative stress conditions. We subjected CSB-deficient human fibroblasts (CS-B) and control fibroblasts to acute and chronic oxidative stress through hydrogen peroxide (H2O2) treatment and elevated oxygen levels. Our findings reveal that CS-B fibroblasts exhibit a distinct resistance to acute oxidative stress, as evidenced by their sustained viability and minimal cell cycle arrest compared to control fibroblasts. However, chronic oxidative conditions led to accelerated senescence in CS-B fibroblasts, demonstrated by increased telomere attrition rates, senescent morphology, and upregulated senescence-associated {beta}-galactosidase activity. Further, gene expression analysis post-H2O2 exposure identified the downregulation of key DNA repair and cell cycle genes in CS-B fibroblasts, suggesting a compromised ability to respond to oxidative DNA damage. These observations underscore the multifaceted role of CSB in genomic maintenance and highlight its potential involvement in the pathology of CS through impaired response to oxidative stress and telomere instability. The study contributes to a deeper understanding of the cellular mechanisms that underlie CS symptoms and may inform potential therapeutic strategies targeting oxidative damage repair systems.