Therapy-induced APOBEC3A drives evolution of persistent cancer cells

Isozaki, Hideko; Sakhtemani, Ramin; Abbasi, Ammal; Nikpour, Naveed; Stanzione, Marcello; Oh, Sunwoo; Langenbucher, Adam; Monroe, Susanna; Su, Wen; Cabanos, Heidie Frisco; Siddiqui, Faria M.; Phan, Nicole; Jalili, Pégah; Timonina, Daria; Bilton, Samantha; Gomez‐Caraballo, María; Archibald, Hannah L.; Nangia, Varuna; Dionne, Kristin; Riley, Amanda A.; Lawlor, Matthew A.; Banwait, Mandeep K.; Cobb, Rosemary; Zou, Lee; Dyson, Nicholas J.; Ott, Christopher J.; Benes, Cyril H.; Getz, Gad; Chan, Chang S.; Shaw, Alice T.; Gainor, Justin F.; Lin, Jessica J.; Sequist, Lecia V.; Piotrowska, Zofia; Yeap, Beow Y.; Engelman, Jeffrey A.; Lee, Jake June-Koo; Maruvka, Yosef E.; Buisson, Rémi; Lawrence, Michael S.; Hata, Aaron N.

doi:10.1038/s41586-023-06303-1

Cited by 65 publications

(32 citation statements)

References 65 publications

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“…The unique mutation signature of A3C has some interesting implications. Explorations of the role of APOBEC3 proteins in mutating cancer genomes have largely focused on APOBEC3A and 3B (Burns et al 2013a;Taylor et al 2013;Alexandrov et al 2013;Chan et al 2015;Petljak et al 2021Petljak et al , 2022Isozaki et al 2023;Caswell et al 2023), with some attention paid to APOBEC3H haplotype I (Starrett et al 2016), APOBEC3G (Liu et al 2023), and APOBEC3C (Qian et al 2022). Indeed, recent analyses indicate that APOBEC3A is the predominant mutator of cancer genomes, with a lesser role for APOBEC3B (Petljak et al 2022), although the relative contributions likely vary in different contexts (Carpenter et al 2023).…”

Section: Discussionmentioning

confidence: 99%

The cytidine deaminase APOBEC3C has unique sequence and genome feature preferences

Brown

2024

Preprint

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APOBEC proteins are cytidine deaminases that restrict the replication of viruses and transposable elements. Several members of the APOBEC3 family, APOBEC3A, APOBEC3B, and APOBEC3H-I, can access the nucleus and cause what is thought to be indiscriminate deamination of the genome, resulting in mutagenesis and genome instability. Although APOBEC3C is also present in the nucleus, its deamination target preferences are unknown. By expressing human APOBEC3C in a yeast model system, I have defined the APOBEC3C mutation signature, as well as the preferred genome features of APOBEC3C targets. The APOBEC3C mutation signature is distinct from those of the known cancer genome mutators APOBEC3A and APOBEC3B. APOBEC3C produces DNA strand-coordinated mutation clusters, and APOBEC3C mutations are enriched near the transcription start sites of active genes. Surprisingly, APOBEC3C lacks the bias for the lagging strand of DNA replication that is seen for APOBEC3A and APOBEC3B. The unique preferences of APOBEC3C constitute a mutation profile that will be useful in defining sites of APOBEC3C mutagenesis in human genomes.

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Section: Discussionmentioning

confidence: 99%

The cytidine deaminase APOBEC3C has unique sequence and genome feature preferences

Brown

2024

Preprint

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“…The SBS13 signature creates resistance mutation in some non-small cell lung cancers during targeted therapy 79 . Mutations that impart tyrosine kinase inhibitor resistance are found in EGFR (C797S: T G C to T C C) 79 and ALK (S1206C:T C C to T G C; L1122V: C TG to G TG; G1269A: G G A to G C A) 79 . Therefore, understanding how error-prone repair is triggered can impact intervention strategies.…”

Section: Discussionmentioning

confidence: 99%

“…Error-prone uracil repair has implications for cancer evolution and drug resistance development [78][79][80] . COSMIC signature SBS13 is one relevant case 8,9 .…”

Section: Discussionmentioning

confidence: 99%

UNG-RPA interaction governs the choice between high-fidelity and mutagenic uracil repair

Mu,

Chen,

Plummer

et al. 2024

Preprint

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Mammalian Uracil DNA glycosylase (UNG) removes uracils and initiates high-fidelity base excision repair to maintain genomic stability. During B cell development, activation-induced cytidine deaminase (AID) creates uracils that UNG processes in an error-prone fashion to accomplish immunoglobulin (Ig) somatic hypermutation (SHM) or class switch recombination (CSR). The mechanism that governs high-fidelity versus mutagenic uracil repair is not understood. The B cell tropic gammaherpesvirus (GHV) encodes a functional homolog of UNG that can process AID induced genomic uracils. GHVUNG does not support hypermutation, suggesting intrinsic properties of UNG influence repair outcome. Noting the structural divergence between the UNGs, we define the RPA interacting motif as the determinant of mutation outcome. UNG or RPA mutants unable to interact with each other, only support high-fidelity repair. In B cells, transversions at the Ig variable region are abated while CSR is supported. Thus UNG-RPA governs the generation of mutations and has implications for locus specific mutagenesis in B cells and deamination associated mutational signatures in cancer.

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“…At the regional scale, APOBEC3 mutagenesis is more pronounced in tissue-specific open-chromatin regions (50,51), indicating that the SGMs preferentially occur in actively expressed genes in which LOF mutations are more likely to have functional consequences. Last, mutational processes that generate SGMs and cause increased tumor heterogeneity may be reined in through therapeutic APOBEC3 inhibition (52), especially as APOBEC3 activity later in tumor evolution has been linked to subclonal diversification, driver mutations, and resistance to targeted therapy (39,53,54).…”

Section: Discussionmentioning

confidence: 99%

Mutational processes of tobacco smoking and APOBEC activity generate protein-truncating mutations in cancer genomes

Adler,

Bahcheli,

Cheng

et al. 2023

Sci. Adv.

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Mutational signatures represent a genomic footprint of endogenous and exogenous mutational processes through tumor evolution. However, their functional impact on the proteome remains incompletely understood. We analyzed the protein-coding impact of single-base substitution (SBS) signatures in 12,341 cancer genomes from 18 cancer types. Stop-gain mutations (SGMs) (i.e., nonsense mutations) were strongly enriched in SBS signatures of tobacco smoking, APOBEC cytidine deaminases, and reactive oxygen species. These mutational processes alter specific trinucleotide contexts and thereby substitute serines and glutamic acids with stop codons. SGMs frequently affect cancer hallmark pathways and tumor suppressors such as TP53 , FAT1 , and APC . Tobacco-driven SGMs in lung cancer correlate with smoking history and highlight a preventable determinant of these harmful mutations. APOBEC-driven SGMs are enriched in YTCA motifs and associate with APOBEC3A expression. Our study exposes SGM expansion as a genetic mechanism by which endogenous and carcinogenic mutational processes directly contribute to protein loss of function, oncogenesis, and tumor heterogeneity.

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Therapy-induced APOBEC3A drives evolution of persistent cancer cells

Cited by 65 publications

References 65 publications

The cytidine deaminase APOBEC3C has unique sequence and genome feature preferences

The cytidine deaminase APOBEC3C has unique sequence and genome feature preferences

UNG-RPA interaction governs the choice between high-fidelity and mutagenic uracil repair

Mutational processes of tobacco smoking and APOBEC activity generate protein-truncating mutations in cancer genomes

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