A prevalent cancer susceptibility APOBEC3A hybrid allele bearing APOBEC3B 3′UTR enhances chromosomal DNA damage
A prevalent cancer susceptibility APOBEC3A hybrid allele bearing APOBEC3B 3′UTR enhances chromosomal DNA damage
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DOI：
10.1038/ncomms6129
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发表时间：
2014-10-01
影响因子：
16.6
通讯作者：
Wain-Hobson, Simon
中科院分区：
文献类型：
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作者：
Caval, Vincent;Suspene, Rodolphe;Wain-Hobson, Simon
人APOBEC 3A（A3 A）胞苷脱氨酶是一种可以将突变引入染色体DNA的宿主酶。由于APOBEC 3B（A3 B）编码的C-末端催化结构域与A3 A相似，91%相同，因此我们检查了其遗传毒性潜力以及高度流行的嵌合A3 A-A3 B缺失等位基因（Delta A3 B）的遗传毒性潜力，该等位基因与乳腺癌，卵巢癌和肝癌的发生率较高有关。有趣的是，来自Delta A3 B（-/-）患者的乳腺癌基因组显示出更高的总体突变负担。这里显示，生殖系A3 B可以使核DNA超突变，尽管效率低于A3 A。由Delta A3 B产生的嵌合A3 A mRNA更稳定，导致更高的细胞内A3 A水平和更大的DNA损伤。鉴于东南亚Delta A3 B等位基因的高渗透率，较高的A3 A水平所暗示的癌症负担可能相当大。
Human APOBEC3A (A3A) cytidine deaminase is a host enzyme that can introduce mutations into chromosomal DNA. As APOBEC3B (A3B) encodes a C-terminal catalytic domain similar to 91% identical to A3A, we examined its genotoxic potential as well as that of a highly prevalent chimaeric A3A-A3B deletion allele (Delta A3B), which is linked to a higher odds ratio of developing breast, ovarian and liver cancer. Interestingly, breast cancer genomes from Delta A3B(-/-) patients show a higher overall mutation burden. Here it is shown that germline A3B can hypermutate nuclear DNA, albeit less efficiently than A3A. Chimaeric A3A mRNA resulting from Delta A3B was more stable, resulting in higher intracellular A3A levels and greater DNA damage. The cancer burden implied by the higher A3A levels could be considerable given the high penetration of the Delta A3B allele in South East Asia.