Influence of chromatin remodeling in the removal of UVC-induced damage in TCR proficient and deficient Chinese hamster cells.

In mammalian cells, nucleotide excision repair system is constituted of two sub-pathways, global genomic repair (GGR) and transcription coupled repair (TCR). Deficiency of TCR pathway leads to Cockyane syndrome (CS) which is a rare human autosomal recessive disorder. Owing to the pivotal role of CSB gene in TCR, it's mutation causes severe repair and transcriptional defects in CSB patients. CSB protein belongs to the ATP chromatin remodeling complex, hence presumably an improper chromatin remodeling in CSB cells could be at the source of inefficient removal of pyrimidine dimers (CPDs) after UVC exposure in these patients. In this study, we evaluated the role of chromatin remodeling process on UVC induced CPDs and the ensuing effect on chromosomal aberrations in UV61 cells (TCR deficient) and its parental cell line, AA8 (TCR proficient). We observed that post 2 h UVC irradiation, both cell lines underwent pronounced chromatin relaxation but was lower in CSB deficient UV61 cells. Since the deficiency in chromatin remodeling in CSB-mutated cells was accompanied by a decrease in the histone acetylation level, the histone deacetylase inhibitor trichostatin A (TSA) was employed to improve the removal of UVC-induced lesions by increasing the histone acetylation level. Contrary to expectations, TSA increased the induction of chromosomal aberrations and apoptotic cells along with amounts of CPDs after UVC-irradiation, indicating that changes in histone acetylation levels might contribute to the failure in the removal of UVC-induced lesions. Also, it has been shown earlier that the expression of genes regulated by CSB is affected by the increase in the acetylation level produced by TSA. Taken all together, we hypothesize that failure in the removal of UVC induced lesions in CSB-deficient cells can be caused by an imbalance in histone acetylation levels leading to chromatin conformation changes and hence interaction defects among repair proteins and DNA lesions.