Alternative splicing of APOBEC3D generates functional diversity and its role as a DNA mutator

Details

• Alternative Title:
  Int J Hematol
• Personal Author:
  Takei, Hisashi ; Fukuda, Hirofumi ; Pan, Gilbert ; Yamazaki, Hiroyuki ; Matsumoto, Tadahiko ; Kazuma, Yasuhiro ; Fujii, Masanori ; Nakayama, Sohei ; Kobayashi, Ikei S ; Shindo, Keisuke ; Yamashita, Riu ; Shirakawa, Kotaro ; Takaori-Kondo, Akifumi ; Kobayashi, Susumu S.
• Description:
  The apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) protein family members have cytidine deaminase activity and can induce cytosine to uracil transition in nucleic acid. The main function of APOBEC3 (A3) proteins is to trigger an innate immune response to viral infections. Recent reports have shown that several APOBEC family proteins such as A3B can induce somatic mutations into genomic DNA and thus promote cancer development. However, the role of A3D on somatic mutations is unclear. Here, we identified the alternative splicing of A3D, and investigated each splice variant's subcellular localization and role in DNA mutagenesis. We identified four A3D variants, which all have one or two cytidine deaminase domains. The full-length form of A3D (variant 1) and truncated forms of A3D (variant 2, 6, 7) showed the ability to induce C/G to T/A transitions in foreign DNA and genomic DNA and retained antiretroviral activity. Furthermore, we demonstrated that A3D and A3B could induce deletions that are possibly repaired by microhomology-mediated end joining (MMEJ). Taken together, our experiments illustrated that alternative splicing generates functional diversity of A3D, and some variants can act as DNA mutators in genomic DNA.
• Subjects:
  Alternative Splicing Anti-Retroviral Agents Cell Line, Tumor Cells, Cultured Cytidine Deaminase DNA DNA End-Joining Repair Genetic Variation Humans Mutation Protein Domains

  More +
• Keywords:
  Apolipoprotein B MRNA Editing Enzyme Catalytic Polypeptide-Like 3D (APOBEC3D) Cytidine Deaminase Leukemia Mutations Resistance
• Source:
  Int J Hematol. 112(3):395-408
• Pubmed ID:
  32533515
• Pubmed Central ID:
  PMC8713138
• Document Type:
  Journal Article
• Funding:
  R01CA169259/NH/NIH HHSUnited States/ ; R21CA178301/NH/NIH HHSUnited States/ ; RSG-13-047/American Cancer Society/ ; R21 CA178301/CA/NCI NIH HHSUnited States/ ; R01 DP000110/DP/NCCDPHP CDC HHSUnited States/ ; R01 CA169259/CA/NCI NIH HHSUnited States/ ; DP-0110-12-00/Harvard Stem Cell Institute/
• Volume:
  112
• Issue:
  3
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:587b5a42c4d35623d47584c68d59bdd88fa16ad191c178e33d88563730ebda0f
• Download URL:
  https://stacks.cdc.gov/view/cdc/113010/cdc_113010_DS1.pdf
• File Type:
  [PDF - 1.78 MB ]