Prospectively defined patterns of APOBEC3A mutagenesis are prevalent in human cancers

DeWeerd, Rachel A.; Németh, Eszter; Póti, Ádám; Petryk, Nataliya; Chen, Chun-Long; Hyrien, Olivier; Szüts, Dávid; Green, Abby M.

doi:10.1016/j.celrep.2022.110555

Cited by 36 publications

(51 citation statements)

References 78 publications

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“…This -2 pyrimidine bias mirrors recent WGS results from human A3Ainduced murine hepatocellular carcinomas (70% YTCW [71]), and it also resembles the bias reported originally for human A3A expression in yeast [50,51]. It also mirrors a strong -2 pyrimidine bias reported for A3A in the chicken B cell line DT40 published during preparation of this manuscript [79]. However, importantly, A3B also shows a modest YTCW bias here in human cells, which is different from the RTCW bias reported in yeast [50,51].…”

Section: Discussionsupporting

confidence: 86%

Mutational impact of APOBEC3A and APOBEC3B in a human cell line and comparisons to breast cancer

Jarvis

Carpenter

Temiz

et al. 2022

Preprint

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A prominent source of mutation in cancer is single-stranded DNA cytosine deamination by cellular APOBEC3 enzymes, which results in C-to-T and C-to-G mutations in TCA and TCT motifs. Although multiple enzymes have been implicated, reports conflict and it is unclear which enzyme(s) are responsible. Here we develop a selectable system to quantify genome mutation and compare the mutagenic activities of three leading candidates - APOBEC3A, APOBEC3B, and APOBEC3H. The human cell line, HAP1, was engineered to express the thymidine kinase (TK) gene of HSV-1, which confers sensitivity to ganciclovir. Clonal expression of APOBEC3A and APOBEC3B, but not catalytic mutant controls or APOBEC3H, triggered elevated DNA damage responses and increased frequencies of TK mutation. Mutant TK DNA sequences revealed nearly indistinguishable cytosine mutation patterns. Whole genome sequences from TK mutant clones confirmed these results and enabled broader bioinformatic analyses. Most importantly, comparisons of “pure” APOBEC3A- and APOBEC3B-inflicted mutation signatures from this system and the actual APOBEC3 signature from breast cancer indicated that most tumors manifest a composite signature. These studies help resolve a long-standing etiologic debate in the cancer field and indicate that future diagnostic and therapeutic efforts should focus on both APOBEC3A and APOBEC3B.

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Section: Discussionsupporting

confidence: 86%

Mutational impact of APOBEC3A and APOBEC3B in a human cell line and comparisons to breast cancer

Jarvis

Carpenter

Temiz

et al. 2022

Preprint

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“…The observed sequence context is consistent with editing being mediated by APOBEC3F (6) or APOBEC3A (7, 8). Both enzymes are present in the cytoplasm (or shuffle between the nucleus and the cytoplasm) (5), where poxvirus replication occurs.…”

Section: Resultssupporting

confidence: 76%

“…In cancer genomes, there is little evidence for transcriptional asymmetry of APOBEC3A-induced mutations (8). Conversely, replication asymmetry is observed, with most mutations occurring on the lagging strand (8). APOBEC editing of human papillomavirus and of plasmid DNA instead occurs on both strands (9, 11).…”

Section: Resultsmentioning

confidence: 99%

Genomic clustering and sequence context of mutations in human monkeypox virus (hMPXV1) genomes

Forni

Cagliani

Pozzoli

et al. 2022

Preprint

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The ongoing worldwide monkeypox outbreak is caused by viral lineages (globally referred to as hMPXV1) that are related to but distinct from clade IIb MPXV viruses transmitted in Nigeria. Analysis of genetic differences indicated that APOBEC-mediated editing might be responsible for the unexpectedly high number of mutations observed in hMPXV1 genomes. Here, using 1624 hMPXV1 publicly available sequences, we analyzed mutations that accrued since 2017 until the emergence of the current predominant variant (B.1), as well as those that that have been accumulating during the 2022 outbreak. We found that substitutions tend to cluster and mutational hot-spots are observed. Investigation of the sequence context of C to T changes indicated a preference for 5'-TCA/G-3' motifs, suggesting APOBEC3F- or APOBEC3A-mediated editing. The sequence context has remained unchanged since 2017, indicating that the same mutational mechanism that is driving the accumulation of substitutions during the ongoing human-to-human transmission, was already operating before the virus left Africa. We suggest that APOBEC3A is the most likely candidate, given its expression in the skin and its known role in the editing of human papillomavirus.

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“…Research in model systems and multiple associations has implicated APOBEC3 deaminases in cancer mutagenesis 3 , 13 , 44 . Here, by deleting candidate APOBEC3 mutators from human cancer cell lines that generate the relevant mutations naturally over time 4 , we provide causal evidence for the hypothesis put forward two decades ago that APOBEC3 enzymes can act as endogenous sources of mutation in cancer 6 .…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of APOBEC3 mutagenesis in human cancer cells

Petljak

Dananberg

Chu

et al. 2022

Nature

153

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The APOBEC3 family of cytosine deaminases has been implicated in some of the most prevalent mutational signatures in cancer1–3. However, a causal link between endogenous APOBEC3 enzymes and mutational signatures in human cancer genomes has not been established, leaving the mechanisms of APOBEC3 mutagenesis poorly understood. Here, to investigate the mechanisms of APOBEC3 mutagenesis, we deleted implicated genes from human cancer cell lines that naturally generate APOBEC3-associated mutational signatures over time4. Analysis of non-clustered and clustered signatures across whole-genome sequences from 251 breast, bladder and lymphoma cancer cell line clones revealed that APOBEC3A deletion diminished APOBEC3-associated mutational signatures. Deletion of both APOBEC3A and APOBEC3B further decreased APOBEC3 mutation burdens, without eliminating them. Deletion of APOBEC3B increased APOBEC3A protein levels, activity and APOBEC3A-mediated mutagenesis in some cell lines. The uracil glycosylase UNG was required for APOBEC3-mediated transversions, whereas the loss of the translesion polymerase REV1 decreased overall mutation burdens. Together, these data represent direct evidence that endogenous APOBEC3 deaminases generate prevalent mutational signatures in human cancer cells. Our results identify APOBEC3A as the main driver of these mutations, indicate that APOBEC3B can restrain APOBEC3A-dependent mutagenesis while contributing its own smaller mutation burdens and dissect mechanisms that translate APOBEC3 activities into distinct mutational signatures.

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Prospectively defined patterns of APOBEC3A mutagenesis are prevalent in human cancers

Cited by 36 publications

References 78 publications

Mutational impact of APOBEC3A and APOBEC3B in a human cell line and comparisons to breast cancer

Mutational impact of APOBEC3A and APOBEC3B in a human cell line and comparisons to breast cancer

Genomic clustering and sequence context of mutations in human monkeypox virus (hMPXV1) genomes

Mechanisms of APOBEC3 mutagenesis in human cancer cells

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