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Mesoscale DNA features impact APOBEC3A and APOBEC3B deaminase activity and shape tumor mutational landscapes.
Sanchez, Ambrocio; Ortega, Pedro; Sakhtemani, Ramin; Manjunath, Lavanya; Oh, Sunwoo; Bournique, Elodie; Becker, Alexandrea; Kim, Kyumin; Durfee, Cameron; Temiz, Nuri Alpay; Chen, Xiaojiang S; Harris, Reuben S; Lawrence, Michael S; Buisson, Rémi.
Afiliação
  • Sanchez A; Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA.
  • Ortega P; Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA.
  • Sakhtemani R; Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA.
  • Manjunath L; Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA.
  • Oh S; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Bournique E; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Becker A; Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA.
  • Kim K; Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA.
  • Durfee C; Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA.
  • Temiz NA; Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA.
  • Chen XS; Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA.
  • Harris RS; Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA.
  • Lawrence MS; Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA.
  • Buisson R; Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA.
Nat Commun ; 15(1): 2370, 2024 Mar 18.
Article em En | MEDLINE | ID: mdl-38499542
ABSTRACT
Antiviral DNA cytosine deaminases APOBEC3A and APOBEC3B are major sources of mutations in cancer by catalyzing cytosine-to-uracil deamination. APOBEC3A preferentially targets single-stranded DNAs, with a noted affinity for DNA regions that adopt stem-loop secondary structures. However, the detailed substrate preferences of APOBEC3A and APOBEC3B have not been fully established, and the specific influence of the DNA sequence on APOBEC3A and APOBEC3B deaminase activity remains to be investigated. Here, we find that APOBEC3B also selectively targets DNA stem-loop structures, and they are distinct from those subjected to deamination by APOBEC3A. We develop Oligo-seq, an in vitro sequencing-based method to identify specific sequence contexts promoting APOBEC3A and APOBEC3B activity. Through this approach, we demonstrate that APOBEC3A and APOBEC3B deaminase activity is strongly regulated by specific sequences surrounding the targeted cytosine. Moreover, we identify the structural features of APOBEC3B and APOBEC3A responsible for their substrate preferences. Importantly, we determine that APOBEC3B-induced mutations in hairpin-forming sequences within tumor genomes differ from the DNA stem-loop sequences mutated by APOBEC3A. Together, our study provides evidence that APOBEC3A and APOBEC3B can generate distinct mutation landscapes in cancer genomes, driven by their unique substrate selectivity.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas / Neoplasias Limite: Humans Idioma: En Revista: Nat Commun Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas / Neoplasias Limite: Humans Idioma: En Revista: Nat Commun Ano de publicação: 2024 Tipo de documento: Article