A hallmark of cancer is genomic instability, which can enable cancer cells to evade therapeutic strategies. Here we employed a computational approach to uncover mechanisms underlying cancer mutational burden by focusing upon relationships between 1) translocation breakpoints and the thousands of G4 DNA-forming sequences within retrotransposons impacting transcription and exemplifying probable non-B DNA structures and 2) transcriptome profiling and cancer mutations. We determined the location and number of G4 DNA-forming sequences in the Genome Reference Consortium Human Build 38 and found a total of 358,605 covering similar to 13.4 million bases. By analyzing >97,000 unique translocation breakpoints from the Catalogue Of Somatic Mutations In Cancer (COSMIC), we found that breakpoints are overrepresented at G4 DNA-forming sequences within hominid-specific SVA retrotransposons, and generally occur in tumors with mutations in tumor suppressor genes, such as TP53. Furthermore, correlation analyses between mRNA levels and exome mutational loads from The Cancer Genome Atlas (TCGA) encompassing >450,000 gene-mutation regressions revealed strong positive and negative associations, which depended upon tissue of origin. The strongest positive correlations originated from genes not listed as cancer genes in COSMIC; yet, these show strong predictive power for survival in most tumor types by Kaplan-Meier estimation. Thus, correlation analyses of DNA structure and gene expression with mutation loads complement and extend more traditional approaches to elucidate processes shaping genomic instability in cancer. The combined results point to G4 DNA, activation of cell cycle/DNA repair pathways, and mitochondrial dysfunction as three major factors driving the accumulation of somatic mutations in cancer cells. (C) 2019 The Authors. Published by Elsevier Ltd.

A large number of SNF2 family, DNA and ATP-dependent motor proteins are needed during transcription, DNA replication, and DNA repair to manipulate protein-DNA interactions and change DNA structure. SMARCAL1, ZRANB3, and HLTF are three related members of this family with specialized functions that maintain genome stability during DNA replication. These proteins are recruited to replication forks through protein-protein interactions and bind DNA using both their motor and substrate recognition domains (SRDs). The SRD provides specificity to DNA structures like forks and junctions and confers DNA remodeling activity to the motor domains. Remodeling reactions include fork reversal and branch migration to promote fork stabilization, template switching, and repair. Regulation ensures these powerful activities remain controlled and restricted to damaged replication forks. Inherited mutations in SMARCAL1 cause a severe developmental disorder and mutations in ZRANB3 and HLTF are linked to cancer illustrating the importance of these enzymes in ensuring complete and accurate DNA replication. In this review, we examine how these proteins function, concentrating on their common and unique attributes and regulatory mechanisms.

A large number of SNF2 family, DNA and ATP-dependent motor proteins are needed during transcription, DNA replication, and DNA repair to manipulate protein-DNA interactions and change DNA structure. SMARCAL1, ZRANB3, and HLTF are three related members of this family with specialized functions that maintain genome stability during DNA replication. These proteins are recruited to replication forks through protein-protein interactions and bind DNA using both their motor and substrate recognition domains (SRDs). The SRD provides specificity to DNA structures like forks and junctions and confers DNA remodeling activity to the motor domains. Remodeling reactions include fork reversal and branch migration to promote fork stabilization, template switching, and repair. Regulation ensures these powerful activities remain controlled and restricted to damaged replication forks. Inherited mutations in SMARCAL1 cause a severe developmental disorder and mutations in ZRANB3 and HLTF are linked to cancer illustrating the importance of these enzymes in ensuring complete and accurate DNA replication. In this review, we examine how these proteins function, concentrating on their common and unique attributes and regulatory mechanisms.