DNA錯配修復促進APOBEC3介導的瀰漫型超突變

DNA錯配修復促進APOBEC3介導的瀰漫型超突變

作者：

小柯機器人

發布時間：2020/8/4 18:00:16

西班牙巴塞隆納科學技術學院Fran Supek研究組取得一項新突破。他們的最新研究發現在癌症患者中DNA錯配修復促進APOBEC3（A3）介導的瀰漫型超突變。2020年8月3日，國際學術期刊《自然-遺傳學》發表了這一成果。

研究人員對腫瘤基因組中聚集誘變的不同模式進行了分類，從而確定了一種新的A3模式：非周期性、彌散型超突變（omikli）。該機制獨立於已知的局灶型超突變（kataegis），並與DNA錯配修復途徑的活性有關，該途徑可提供A3所需的單鏈DNA底物，並在整個基因組範圍內有助於A3突變的產生。

因為錯配修復是針對DNA複製前期、富含基因的染色體結構域，所以A3誘變具有產生廣泛影響突變的可能。這超過了其他常見的致癌物，例如二手菸和紫外線照射。細胞將其DNA修復能力引導至更重要的基因組區域。因此，破壞DNA修復的致癌物可能是非常有效的治療藥物。

據了解，某些誘變劑可以在單個遺傳事件中產生多種遺傳變化，如APOBEC3胞嘧啶脫氨酶。A3激活導致在DNA斷裂點附近發生「突變庫」。然而，對於大多數A3突變的潛在機制了解甚少。

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