Alternative splicing of APOBEC3D generates functional diversity and its role as a DNA mutator
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ORIGINAL ARTICLE
Alternative splicing of APOBEC3D generates functional diversity and its role as a DNA mutator Hisashi Takei1,2 · Hirofumi Fukuda3 · Gilbert Pan1 · Hiroyuki Yamazaki3 · Tadahiko Matsumoto3 · Yasuhiro Kazuma3 · Masanori Fujii1 · Sohei Nakayama1 · Ikei S. Kobayashi1 · Keisuke Shindo3 · Riu Yamashita4 · Kotaro Shirakawa3 · Akifumi Takaori‑Kondo3 · Susumu S. Kobayashi1,5,6 Received: 7 November 2019 / Revised: 8 May 2020 / Accepted: 29 May 2020 © Japanese Society of Hematology 2020
Abstract 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. Keywords Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3D (APOBEC3D) · Mutations · Cytidine deaminase · Resistance · Leukemia
Introduction The apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) protein family consists of 11 members: APOBEC1, APOBEC2, seven APOBEC3s Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12185-020-02904-y) contains supplementary material, which is available to authorized users. * Susumu S. Kobayashi [email protected] 1
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, E/CLS‑407, 330 Brookline Avenue, Boston, MA 02215, USA
2
Department of Hematology, Gunma University Graduate School of Medicine, 3‑39‑22 Showa‑machi, Maebashi, Gunma 371‑8511, Japan
3
Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin kawahara‑cho, Sakyo‑ku, Kyoto 606‑8507, Japan
(A3s), APOBEC4, and activation-induced cytidine deaminase (AID) [1]. APOBEC1, A3s, and AID possess cytidine deaminase activity and are known to induce a cytosine (C) to uracil (U) transition which causes C to thymine (T) or guanine (G) to adenine (A) transition after DNA replication [2]. APOBEC1 deaminates cytidine to
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