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研究揭示APOBEC3在人类癌细胞中的突变机制
2022-07-24 16:19
来源：小柯机器人

美国斯隆凯特林研究所John Maciejowski等研究人员合作揭示APOBEC3在人类癌细胞中的突变机制。相关论文于2022年7月20日在线发表于国际学术期刊《自然》。

为了研究APOBEC3诱变的机制，研究人员从人类癌症细胞系中删除了牵连的基因，这些基因随着时间的推移自然产生与APOBEC3相关的突变特征。对251个乳腺癌、膀胱癌和淋巴瘤细胞系克隆的全基因组序列中的非聚类和聚类特征的分析显示，APOBEC3A的删除减少了APOBEC3相关的突变特征。APOBEC3A和APOBEC3B的删除进一步降低了APOBEC3的突变负担，但没有消除它们。APOBEC3B的缺失增加了APOBEC3A的蛋白水平、活性和APOBEC3A在一些细胞系中介导的诱变。尿嘧啶糖基化酶UNG是APOBEC3介导的转座所必需的，而转座聚合酶REV1的缺失降低了总体突变负担。
 
总之，这些数据代表了内源性APOBEC3脱氨酶在人类癌症细胞中产生普遍的突变特征的直接证据。这些结果确定APOBEC3A是这些突变的主要驱动力，表明APOBEC3B可以抑制APOBEC3A依赖性的诱变，同时贡献其自身较小的突变负担，并剖析了将APOBEC3活性转化为不同突变特征的机制。
 
据介绍，胞嘧啶脱氨酶的APOBEC3家族已经被关联到一些最普遍的癌症突变特征中。然而，内源性APOBEC3酶与人类癌症基因组中的突变特征之间的因果关系尚未建立，使得人们对APOBEC3的诱变机制了解甚少。
 
附：英文原文
 
Title: Mechanisms of APOBEC3 mutagenesis in human cancer cells

Author: Petljak, Mia, Dananberg, Alexandra, Chu, Kevan, Bergstrom, Erik N., Striepen, Josefine, von Morgen, Patrick, Chen, Yanyang, Shah, Hina, Sale, Julian E., Alexandrov, Ludmil B., Stratton, Michael R., Maciejowski, John

Issue&Volume: 2022-07-20

Abstract: The APOBEC3 family of cytosine deaminases has been implicated in some of the most prevalent mutational signatures in cancer1,2,3. However, a causal link between endogenous APOBEC3 enzymes and mutational signatures in human cancer genomes has not been established, leaving the mechanisms of APOBEC3 mutagenesis poorly understood. Here, to investigate the mechanisms of APOBEC3 mutagenesis, we deleted implicated genes from human cancer cell lines that naturally generate APOBEC3-associated mutational signatures over time4. Analysis of non-clustered and clustered signatures across whole-genome sequences from 251 breast, bladder and lymphoma cancer cell line clones revealed that APOBEC3A deletion diminished APOBEC3-associated mutational signatures. Deletion of both APOBEC3A and APOBEC3B further decreased APOBEC3 mutation burdens, without eliminating them. Deletion of APOBEC3B increased APOBEC3A protein levels, activity and APOBEC3A-mediated mutagenesis in some cell lines. The uracil glycosylase UNG was required for APOBEC3-mediated transversions, whereas the loss of the translesion polymerase REV1 decreased overall mutation burdens. Together, these data represent direct evidence that endogenous APOBEC3 deaminases generate prevalent mutational signatures in human cancer cells. Our results identify APOBEC3A as the main driver of these mutations, indicate that APOBEC3B can restrain APOBEC3A-dependent mutagenesis while contributing its own smaller mutation burdens and dissect mechanisms that translate APOBEC3 activities into distinct mutational signatures.

DOI: 10.1038/s41586-022-04972-y

Source: https://www.nature.com/articles/s41586-022-04972-y

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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