Fig. 1: Mutagenic polymerase compensation.

A UV-induced pyrimidine dimers are efficiently and correctly bypassed by Translesion Synthesis (TLS) using Pol η. In the absence of Pol η, Pol κ, and Pol ι compensate to bypass the lesions leading to a characteristic pattern of C to T transitions and C to A transversions (COSMIC signature SBS7a-c) [3, 4, 145]. B Double-strand breaks (DSBs) or single-strand breaks (SSBs) that are processed to a DSB are efficiently repaired by homologous recombination (HR). Germline or somatic mutation or down-regulation of HR factors including BRCA1, BRCA2, BARD1, or Rad51 underlies HR-deficiency (HRD) found in ovarian and pancreatic tumors [146]. In HR-compromised tumors, compensatory DSB repair by Pol θ generates small insertions and deletions with a characteristic microhomology (MHD) signature categorized as the small Insertions and Deletions 6 and 8 (ID6) signature [19, 103]. C DNA crosslinks are repaired efficiently by the Fanconi anemia (FA) pathway and germline mutations in one of the 7 components of the Fanconi core complex leads to FA, a tumor-prone disorder. A recent study found that the TLS Pol ι is upregulated in FA cells [50] and it will be interesting to determine whether this contributes to patterns of mutations in FA cells. D Activation of the TLS pathway can occur when the replication fork encounters a bulky DNA adduct or an endogenous obstacle to replication such as structured DNA (e.g., a fragile site). The E3 ligase Rad18 mono-ubiquitinates PCNA to recruit the appropriate TLS polymerase to bypass the lesion efficiently. Analysis of TCGA datasets reveals a positive association between RAD18 expression and overall SNV burden in several tumors including lung adenocarcinoma, lung squamous cell carcinoma, and kidney renal clear cell carcinoma (KIRC) (Table 2) [58] suggesting that dysregulation of TLS leads to mutagenesis.