DNA错配修复促进APOBEC3介导的弥漫型超突变

本期文章：《自然—遗传学》：Online/在线发表

西班牙巴塞罗那科学技术学院Fran Supek研究组取得一项新突破。他们的最新研究发现在癌症患者中DNA错配修复促进APOBEC3（A3）介导的弥漫型超突变。2020年8月3日，国际学术期刊《自然-遗传学》发表了这一成果。

研究人员对肿瘤基因组中聚集诱变的不同模式进行了分类，从而确定了一种新的A3模式：非周期性、弥散型超突变（omikli）。该机制独立于已知的局灶型超突变（kataegis），并与DNA错配修复途径的活性有关，该途径可提供A3所需的单链DNA底物，并在整个基因组范围内有助于A3突变的产生。

因为错配修复是针对DNA复制前期、富含基因的染色体结构域，所以A3诱变具有产生广泛影响突变的可能。这超过了其他常见的致癌物，例如二手烟和紫外线照射。细胞将其DNA修复能力引导至更重要的基因组区域。因此，破坏DNA修复的致癌物可能是非常有效的治疗药物。

据了解，某些诱变剂可以在单个遗传事件中产生多种遗传变化，如APOBEC3胞嘧啶脱氨酶。A3激活导致在DNA断裂点附近发生“突变库”。然而，对于大多数A3突变的潜在机制了解甚少。

附：英文原文

Title: DNA mismatch repair promotes APOBEC3-mediated diffuse hypermutation in human cancers

Author: David Mas-Ponte, Fran Supek

Issue&Volume: 2020-08-03

Abstract: Certain mutagens, including the APOBEC3 (A3) cytosine deaminase enzymes, can create multiple genetic changes in a single event. Activity of A3s results in striking ‘mutation showers’ occurring near DNA breakpoints; however, less is known about the mechanisms underlying the majority of A3 mutations. We classified the diverse patterns of clustered mutagenesis in tumor genomes, which identified a new A3 pattern: nonrecurrent, diffuse hypermutation (omikli). This mechanism occurs independently of the known focal hypermutation (kataegis), and is associated with activity of the DNA mismatch-repair pathway, which can provide the single-stranded DNA substrate needed by A3, and contributes to a substantial proportion of A3 mutations genome wide. Because mismatch repair is directed towards early-replicating, gene-rich chromosomal domains, A3 mutagenesis has a high propensity to generate impactful mutations, which exceeds that of other common carcinogens such as tobacco smoke and ultraviolet exposure. Cells direct their DNA repair capacity towards more important genomic regions; thus, carcinogens that subvert DNA repair can be remarkably potent.

DOI: 10.1038/s41588-020-0674-6

Source: https://www.nature.com/articles/s41588-020-0674-6

期刊信息

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：25.455
官方网址：https://www.nature.com/ng/
投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex