XPD protects CTCF-Cohesin binding sites from somatic mutagenesis

Abstract

AbstractXeroderma pigmentosum group D (XPD) is a DNA helicase involved in transcription initiation and nucleotide excision repair. Missense mutations in XPD are putative drivers in bladder cancer (BLCA) and are associated with a specific single base substitution mutational signature. However, the impact of XPD on the genome-wide distribution of somatic mutations remains unexplored. We analysed somatic mutation distribution in whole-genome sequenced (WGS) BLCA samples with (XPD mutant) and without XPD mutations (WT). XPD genotype had a large impact on the distribution of somatic mutations. XPD mutant samples had increased mutation density at open chromatin, including striking mutation hotspots at CTCF-cohesin binding sites (CBS). We validate these findings in additional WGS cohorts and BLCA exomes. Analysis of XPD occupancy and CBS hotspot mutations in other cancer types suggest that XPD protects CBS from DNA damage. Our study implicates XPD in genomic integrity maintenance at topologically-associating domain boundaries marked by CTCF-cohesin binding.