Hypermutation in human cancer genomes: footprints and mechanisms

Roberts, Steven A.; Gordenin, Dmitry A.

doi:10.1038/nrc3816

Cited by 368 publications

(348 citation statements)

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“…Recent advances in sequencing technology revealed the landscape of genetic aberrations in human cancers (9). The abundant information on mutation signatures in various cancers provides a clue to the molecular processes involved in genetic aberrations during carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

MSH2 Dysregulation Is Triggered by Proinflammatory Cytokine Stimulation and Is Associated with Liver Cancer Development

et al. 2016

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Inflammation predisposes to tumorigenesis in various organs by potentiating a susceptibility to genetic aberrations. The mechanism underlying the enhanced genetic instability through chronic inflammation, however, is not clear. Here, we demonstrated that TNFa stimulation induced transcriptional downregulation of MSH2, a member of the mismatch repair family, via NF-kBdependent miR-21 expression in hepatocytes. Liver cancers developed in ALB-MSH2 À/À AID þ , ALB-MSH2

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Section: Introductionmentioning

confidence: 99%

MSH2 Dysregulation Is Triggered by Proinflammatory Cytokine Stimulation and Is Associated with Liver Cancer Development

et al. 2016

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“…Many of the mutations in human tumors display "signatures" of APOBEC3 family deaminases (33,34). In particular, a signature defined by C to T or C to G mutations in TCW context (W is A or T) is found in the genomes of a number of different cancers and is attributed to mutations caused by APOBEC3 enzymes (33,35,36). As in E. coli, C:G to T:A mutations in tumors would be caused when uracils created in LGST by one of the APOBEC3s are copied by the replicative DNA polymerases δ, or when AP sites created by the excision of uracils by UNG2 are copied by polymerase η, resulting in an insertion of adenines (37).…”

mentioning

confidence: 99%

Strand-biased cytosine deamination at the replication fork causes cytosine to thymine mutations in Escherichia coli

Bhagwat

Hao

Townes

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The rate of cytosine deamination is much higher in single-stranded DNA (ssDNA) than in double-stranded DNA, and copying the resulting uracils causes C to T mutations. To study this phenomenon, the catalytic domain of APOBEC3G (A3G-CTD), an ssDNA-specific cytosine deaminase, was expressed in an Escherichia coli strain defective in uracil repair (ung mutant), and the mutations that accumulated over thousands of generations were determined by whole-genome sequencing. C:G to T:A transitions dominated, with significantly more cytosines mutated to thymine in the lagging-strand template (LGST) than in the leading-strand template (LDST). This strand bias was present in both repair-defective and repair-proficient cells and was strongest and highly significant in cells expressing A3G-CTD. These results show that the LGST is accessible to cellular cytosine deaminating agents, explains the well-known GC skew in microbial genomes, and suggests the APOBEC3 family of mutators may target the LGST in the human genome.uracil-DNA glycosylase | APOBEC3A | APOBEC3B | kataegis | cancer genome mutations P airing of complementary DNA strands protects the DNA bases against modification by a number of hydrolytic, oxidizing, and alkylating chemicals (1-4). For example, water reacts with cytosine, creating uracil, and the rate of this reaction in single-stranded DNA (ssDNA) is more than 100-fold the rate in double-stranded DNA [dsDNA (5-7)]. Uracil-DNA glycosylase (Ung) excises uracils created by cytosine deamination in both ssDNA and dsDNA, resulting in abasic (AP) sites. In dsDNA, the AP sites are replaced with cytosines as a result of copying of the guanine in the complementary strand during repair by the base-excision repair (BER) pathway (8). In contrast, cytosine deaminations occurring in ssDNA are problematic because the complementary strand is not available to the BER pathway. Uracils that escape repair create C:G to T:A mutations, and incomplete repair of uracils can result in persistent AP sites and strand breaks that can destabilize the genome. Hence, identifying ssDNA regions that are susceptible to damage will increase our understanding of causes of mutations and genome instability.The AID/APOBEC (activation-induced deaminase/apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) family of DNA-cytosine deaminases are specific for ssDNA (9, 10). They are found only in vertebrates and are good probes of ssDNA in cells because of their relatively small size (about 190-amino acid catalytic domain). They are active in heterologous hosts such as Escherichia coli (11, 12) and yeast (13-15) and cause mutations in the same sequence context as in their known targets, such as Ig genes and the DNA copy of HIV-1 genome (11,16,17). In particular, the catalytic domain of human APOBEC3G (A3G-CTD) was expressed in an engineered yeast strain lacking the UNG gene and was shown to target ssDNA generated through aberrant resection of telomeric ends (13).To similarly probe ssDNA in E. coli, we expressed A3G-CTD on a plasmid (pA3G-CTD) in...

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“…UV mutation signatures have been described in melanomas and non-melanoma skin cancers (Pfeifer et al, 2012;Griewank et al 2013, Roberts et al, 2014.…”

Section: Mechanistic Studiesmentioning

confidence: 99%