CSB and XPA are inherited diseases characterized by UV hypersensitivity, high skin cancer risk (XPA), and premature aging, which are thought to be caused by defective repair of nuclear DNA (nucleotide excision repair; NER). There is, however, increasing evidence that the CSB and XPA proteins have important functions beyond their role in NER.
Using CSB-deficient human fibroblasts, Caenorabditis elegans, and mice, we showed that CSB promotes acetylation of alpha-tubulin and thereby regulates autophagy. At the organ level, chronic exposure of csbm/m mice to UVA radiation caused a severe skin phenotype with loss of subcutaneous fat, inflammation, and fibrosis. These changes were associated with an accumulation of autophagic/lysosomal proteins and reduced amounts of acetylated alpha-tubulin. At the cellular level, we found that CSB directly interacts with the histondeacetylase 6 (HDAC6) and the alpha-tubulin acetyltransferase ME-17. Administration of the pan-HDAC inhibitor SAHA improved autophagic function in CSB-deficient models from all three species, and rescued the skin phenotype in csbm/m mice. HDAC inhibition may thus represent a therapeutic option for this incurable disease.
Given the importance of symptoms concerning the central nervous system in CSB patients, we are currently employing human induced pluripotent (iPS) cell-derived 3-D neurospheres, brain spheres and brain organoids. In these models we find CSB-deficiency to be associated with endophenotypes, that may underlie the neuropathologies of CSB patients and that some, but not all of these endophenotypes can be improved by SAHA treatment.
XPA is another NER protein with important functions outside the cell nucleus. We have observed that XPA proteins are located inside the mitochondria, and sequencing of mtDNA, RNAseq transcriptome analysis and functional assays suggest XPA to be important for the integrity and function of mitochondria.
Taken together our studies emphasize that NER proteins have important functions beyond their role in nuclear DNA repair.