{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T10:00:36Z","timestamp":1791021636016,"version":"4.1.0"},"reference-count":75,"publisher":"National Academy of Sciences","issue":"31","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"HHS | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["CA269784"],"award-info":[{"award-number":["CA269784"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,8,4]]},"abstract":"<jats:p>\n                    APOBEC3A (A3A) and APOBEC3B (A3B) induce single base substitution signatures SBS2 and SBS13, which are composed of C&gt;T and C&gt;G mutations, respectively, at T\n                    <jats:underline>C<\/jats:underline>\n                    W sequences in &gt;50% of sequenced tumors. However, few driver mutations have been attributed to APOBEC-induced SBS mutations. Although SBS2 and SBS13 have been associated with additional mutation types, the contribution of APOBECs to non-SBS mutations and the mechanisms that generate noncanonical APOBEC-induced mutations are uncharacterized. Here, we show that A3A expression generates non-SBS mutations including C deletions within TT\n                    <jats:underline>C<\/jats:underline>\n                    motifs, CC&gt;TT and T\n                    <jats:underline>C<\/jats:underline>\n                    &gt;AT\/CT\/GT dinucleotide variants (DNVs), distinct classes of paired SNV-SNV events, and complex insertion-SBS mutations in a yeast model system. Furthermore, we found that endogenous APOBEC expression in breast cancer cell lines is a significant driver of all these mutation types. In addition, we show that C deletions and complex insertion-SBS mutations within TT\n                    <jats:underline>C<\/jats:underline>\n                    motifs occur primarily by strand slippage during translesion synthesis (TLS) bypass of APOBEC-induced, UNG-dependent, abasic sites. Additionally, we found that CC&gt;TT and T\n                    <jats:underline>C<\/jats:underline>\n                    &gt;AT\/CT\/GT DNVs, which comprise the APOBEC-associated DBS11 signature, are generated by dU templating and TLS bypass of APOBEC-induced abasic sites, respectively. We also present data indicating that phased APOBEC-induced SNV-SNV mutations are produced during abasic site bypass by TLS. Analysis of WGS data from cultured human cells and tumors indicates that similar mechanisms generate these noncanonical APOBEC-induced mutations in human cancers, providing additional means by which APOBECs could contribute to carcinogenesis and therapeutic resistance.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2609794123","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T17:53:14Z","timestamp":1785261194000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["Distinct repair processes produce APOBEC-induced deletions, tandem substitutions, and complex mutations in yeast and human cells"],"prefix":"10.1073","volume":"123","author":[{"given":"Alexandra","family":"Puzon","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05dk0ce17","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Molecular Biosciences and Center for Reproductive Biology, Washington State University","place":["Pullman"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atri","family":"Raval","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05dk0ce17","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Molecular Biosciences and Center for Reproductive Biology, Washington State University","place":["Pullman"]},{"id":[{"id":"https:\/\/ror.org\/0155zta11","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Molecular Genetics, University of Vermont","place":["Burlington"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron","family":"Cordero","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0155zta11","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Molecular Genetics, University of Vermont","place":["Burlington"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Schiefen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0155zta11","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Molecular Genetics, University of Vermont","place":["Burlington"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2418-0096","authenticated-orcid":false,"given":"Piotr A.","family":"Mieczkowski","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043ehm030","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina","place":["Chapel Hill"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3628-5808","authenticated-orcid":false,"given":"Steven A.","family":"Roberts","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05dk0ce17","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Molecular Biosciences and Center for Reproductive Biology, Washington State University","place":["Pullman"]},{"id":[{"id":"https:\/\/ror.org\/0155zta11","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Molecular Genetics, University of Vermont","place":["Burlington"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9243-4062","authenticated-orcid":false,"given":"Tony M.","family":"Mertz","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05dk0ce17","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Molecular Biosciences and Center for Reproductive Biology, Washington State University","place":["Pullman"]},{"id":[{"id":"https:\/\/ror.org\/0155zta11","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Molecular Genetics, University of Vermont","place":["Burlington"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2020.04.009"},{"key":"e_1_3_4_2_2","first-page":"1","article-title":"The APOBEC3 family of retroelement restriction factors","volume":"371","author":"Refsland E. W.","year":"2013","unstructured":"E. W. Refsland, R. S. Harris, The APOBEC3 family of retroelement restriction factors. Curr. Top. Microbiol. Immunol. 371, 1\u201327 (2013).","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M408802200"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.385161"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.4161\/cc.23713"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkm181"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12918"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11881"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1080\/15384101.2016.1152426"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA119.008053"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-018-0065-9"},{"key":"e_1_3_4_12_2","first-page":"3231","article-title":"Self-cytoplasmic DNA upregulates the mutator enzyme APOBEC3A leading to chromosomal DNA damage","volume":"45","author":"Suspene R.","year":"2017","unstructured":"R. Suspene , Self-cytoplasmic DNA upregulates the mutator enzyme APOBEC3A leading to chromosomal DNA damage. 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Hirota , In vivo evidence for translesion synthesis by the replicative DNA polymerase delta. Nucleic Acids Res. 44, 7242\u20137250 (2016).","journal-title":"Nucleic Acids Res."},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)00145-3"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkn054"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.4842"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14061420"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2019.07.020"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-018-0245-9"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2012.03.030"},{"key":"e_1_3_4_65_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38255-5"},{"key":"e_1_3_4_66_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.16.7160"},{"key":"e_1_3_4_67_2","doi-asserted-by":"publisher","DOI":"10.1016\/bs.mie.2024.11.041"},{"key":"e_1_3_4_68_2","unstructured":"H. Li Aligning sequence reads clone sequences and assembly contigs with BWA-MEM. arXiv [Preprint] (2013) https:\/\/doi.org\/10.48550\/arXiv.1303.3997 (Accessed 1 February 2026)."},{"key":"e_1_3_4_69_2","doi-asserted-by":"crossref","unstructured":"M. Vasimuddin S. Misra H. Li S. Aluru Efficient Architecture-Aware Acceleration of BWA-MEM for Multicore Systems. (IEEE 2019) pp 314\u2013324.","DOI":"10.1109\/IPDPS.2019.00041"},{"key":"e_1_3_4_70_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp352"},{"key":"e_1_3_4_71_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-018-0051-x"},{"key":"e_1_3_4_72_2","unstructured":"A. Puzon Data from \u201cDistinct repair processes produce APOBEC-induced deletions tandem substitutions and complex mutations in yeast and human cells.\u201d NCBI SRA. https:\/\/www.ncbi.nlm.nih.gov\/sra\/?term=PRJNA1420684. Deposited 9 February 2026."},{"key":"e_1_3_4_73_2","doi-asserted-by":"crossref","unstructured":"M. Petljak Data from \u201cMechanisms of APOBEC3 mutagenesis in human cancer cells.\u201d European Nucleotide Archive. https:\/\/www.ebi.ac.uk\/ena\/browser\/view\/ERP137590. Deposited 19 May 2022.","DOI":"10.1038\/s41586-022-04972-y"},{"key":"e_1_3_4_74_2","unstructured":"S. Nik-Zainal Data from \u201cLandscape of somatic mutations in 560 breast cancer whole-genome sequences.\u201d Legacy ICGC 25K Data. https:\/\/docs.icgc-argo.org\/docs\/data-access\/icgc-25k-data. Originally deposited at ICGC 2016. Accessed 2 May 2024."},{"key":"e_1_3_4_75_2","unstructured":"A. Puzon Code for: \u201cDistinct repair processes produce APOBEC-induced deletions tandem substitutions and complex mutations in yeast and human cells.\u201d Zenodo. https:\/\/doi.org\/10.5281\/zenodo.20724527. Deposited 17 June 2026."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2609794123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T17:54:01Z","timestamp":1785261241000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2609794123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,28]]},"references-count":75,"journal-issue":{"issue":"31","published-print":{"date-parts":[[2026,8,4]]}},"alternative-id":["10.1073\/pnas.2609794123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2609794123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,28]]},"assertion":[{"value":"2026-03-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2609794123"}}