Fig. 3: Differential DNA repair and off-target AID deamination underlie mutation hotspots at origins.

Nucleotide excision repair in ultraviolet-irradiated human cells inversely mirrors mutation density at origins in skin melanomas. a Average melanoma mutation density for cluster 1 tumour samples (red line) and strand-resolved XR-seq profiles for CPD (blue lines) in CSB/ERCC6 mutant NHF1 skin fibroblasts at constitutive origins. b Number of mutations at origins as a function of XR-seq signals for CPD (blue line) or 6–4 PP (red line). XR-seq signals were binned by read coverage. Mutation data represent the means and standard errors to the mean of values for each XR-seq signal bin. c Strand-resolved cluster 1 mutational signature contribution to mutagenesis at the origins of cluster 1 tumours. Signature contribution was computed by considering aggregated mutation calls from cluster 1 tumours. Constitutive origins are off-targets for AID deamination in malignant B cell lymphomas. d Consensus contexts of mutations mapped within origin or origin flank domains for cluster 4 tumours. The central position represents the mutated bases. e Fraction of C > T mutations (orange line) or C residues (black line) overlapping the WRCY AID hotspot motif (where W represents weak bases, R purines, C the mutated bases and Y pyrimidines) at origins of cluster 4 tumours. f Pan-cancer origins/origin flanks mutation density ratios as a function of AID (AICDA) expression. Mutation density ratio values were computed for transcript per million (TPM) bins and represent the means and standard errors of the mean.