Cancer genomes harbor numerous genomic alterations and many cancers accumulate thousands of nucleotide sequence variations. A prominent fraction of these mutations arises as a consequence of the off-target activity of DNA/RNA editing cytosine deaminases followed by the replication/repair of edited sites by DNA polymerases (pol), as deduced from the analysis of the DNA sequence context of mutations in different tumor tissues. We have used the weight matrix (sequence profile) approach to analyze mutagenesis due to Activation Induced Deaminase (AID) and two error-prone DNA polymerases. Control experiments using shuffled weight matrices and somatic mutations in immunoglobulin genes confirmed the power of this method. Analysis of somatic mutations in various cancers suggested that AID and DNA polymerases η and θ contribute to mutagenesis in contexts that almost universally correlate with the context of mutations in A:T and G:C sites during the affinity maturation of immunoglobulin genes. Previously, we demonstrated that AID contributes to mutagenesis in (de)methylated genomic DNA in various cancers. Our current analysis of methylation data from malignant lymphomas suggests that driver genes are subject to different (de)methylation processes than non-driver genes and, in addition to AID, the activity of pols η and θ contributes to the establishment of methylation-dependent mutation profiles. This may reflect the functional importance of interplay between mutagenesis in cancer and (de)methylation processes in different groups of genes. The resulting changes in CpG methylation levels and chromatin modifications are likely to cause changes in the expression levels of driver genes that may affect cancer initiation and/or progression.

• Keywords
• computational biology, database, frequency matrices, gene expression, immunoglobulin genes, somatic hypermutation, tumor cells,
• Publication type
• Journal Article MeSH

Mutagenesis is a hallmark and enabling characteristic of cancer cells. The E3 ubiquitin ligase RAD18 and its downstream effectors, the 'Y-family' Trans-Lesion Synthesis (TLS) DNA polymerases, confer DNA damage tolerance at the expense of DNA replication fidelity. Thus, RAD18 and TLS polymerases are attractive candidate mediators of mutagenesis and carcinogenesis. The skin cancer-propensity disorder xeroderma pigmentosum-variant (XPV) is caused by defects in the Y-family DNA polymerase Pol eta (Polη). However it is unknown whether TLS dysfunction contributes more generally to other human cancers. Recent analyses of cancer genomes suggest that TLS polymerases generate many of the mutational signatures present in diverse cancers. Moreover biochemical studies suggest that the TLS pathway is often reprogrammed in cancer cells and that TLS facilitates tolerance of oncogene-induced DNA damage. Here we review recent evidence supporting widespread participation of RAD18 and the Y-family DNA polymerases in the different phases of multi-step carcinogenesis.

• Keywords
• DNA damage, RAD18, cancer, genome maintenance, mutagenesis, trans-lesion synthesis (TLS),
• MeSH
• DNA-Binding Proteins genetics   metabolism   MeSH
• DNA-Directed DNA Polymerase genetics   metabolism   MeSH
• Genome, Human MeSH
• Carcinogenesis genetics   metabolism   pathology   MeSH
• Humans MeSH
• Multigene Family MeSH
• Mutagenesis MeSH
• Neoplasm Proteins genetics   metabolism   MeSH
• Neoplasms genetics   metabolism   pathology   MeSH
• DNA Damage MeSH
• Gene Expression Regulation, Neoplastic * MeSH
• Signal Transduction MeSH
• Ubiquitin-Protein Ligases genetics   metabolism   MeSH
• Xeroderma Pigmentosum genetics   metabolism   pathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH
• Names of Substances
• DNA-Binding Proteins MeSH
• DNA-Directed DNA Polymerase MeSH
• Neoplasm Proteins MeSH
• RAD18 protein, human MeSH Browser
• Rad30 protein MeSH Browser
• Ubiquitin-Protein Ligases MeSH