Alternative splicing of APOBEC3D generates functional diversity and its role as a DNA mutator.
Alternative splicing of APOBEC3D generates functional diversity and its role as a DNA mutator.
复制标题
DOI：
10.1007/s12185-020-02904-y
复制
发表时间：
2020-09
影响因子：
2.1
通讯作者：
Kobayashi SS
中科院分区：
文献类型：
--
作者：
Takei H;Fukuda H;Pan G;Yamazaki H;Matsumoto T;Kazuma Y;Fujii M;Nakayama S;Kobayashi IS;Shindo K;Yamashita R;Shirakawa K;Takaori-Kondo A;Kobayashi SS
载脂蛋白B mrna编辑酶催化多肽样（APOBEC）蛋白家族成员具有胞嘧啶脱氨酶活性，可诱导核酸中胞嘧啶向尿嘧啶转化。APOBEC3 （A3）蛋白的主要功能是触发对病毒感染的先天免疫反应。最近的报道表明，APOBEC家族的一些蛋白如A3B可以诱导体细胞突变进入基因组DNA，从而促进癌症的发展。然而，A3D在体细胞突变中的作用尚不清楚。在这里，我们确定了A3D的备选剪接，并研究了每个剪接变体的亚细胞定位和在DNA突变中的作用。我们确定了四种A3D变体，它们都有一个或两个胞苷脱氨酶结构域。全长形式的A3D（变体1）和截断形式的A3D（变体2、6、7）显示出诱导外源DNA和基因组DNA中C/G向T/A转变的能力，并保留了抗逆转录病毒活性。此外，我们证明A3D和A3B可以诱导缺失，这些缺失可能通过微同源介导的末端连接（MMEJ）修复。综上所述，我们的实验表明，选择性剪接产生了A3D的功能多样性，并且一些变体可以在基因组DNA中充当DNA突变体。
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, 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.
登录
查看更多内容
影响因子：
30.8
作者：
Burns, Michael B.;Temiz, Nuri A.;Harris, Reuben S.
通讯作者：
Harris, Reuben S.
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
50.3
作者：
Klemm L;Duy C;Iacobucci I;Kuchen S;von Levetzow G;Feldhahn N;Henke N;Li Z;Hoffmann TK;Kim YM;Hofmann WK;Jumaa H;Groffen J;Heisterkamp N;Martinelli G;Lieber MR;Casellas R;Müschen M
通讯作者：
Müschen M
影响因子：
--
作者：
Maul, Robert W.;Gearhart, Patricia J.
通讯作者：
Gearhart, Patricia J.
影响因子：
48
作者：
Gibson, Daniel G.;Young, Lei;Smith, Hamilton O.
通讯作者：
Smith, Hamilton O.