染色體碎裂促進癌症中基因擴增的進化
作者：
小柯機器人發布時間：2020/12/25 12:53:46
美國加州大學聖地牙哥分校Don W. Cleveland、Peter J. Campbell等研究人員合作發現，染色體碎裂可促進癌症中基因擴增的進化。2020年12月23日，《自然》雜誌在線發表了這項成果。
研究人員對產生化學治療抗性的克隆細胞分離株進行了全基因組測序，結果表明，通過依賴於聚（ADP-核糖）聚合酶（PARP）和DNA依賴性蛋白激酶（DNA-PKcs）催化亞基的機制，染色體碎裂是環狀染色體外DNA（ecDNA）擴增的主要驅動力 。
縱向分析顯示，通過另外幾輪染色體碎裂，ecDNA的結構進化進一步提高了藥物耐受性。原位Hi-C測序表明，ecDNA優先束縛在染色體末端附近，當存在DNA損傷時它們會重新整合。最初在低水平藥物選擇下形成的染色體內擴增經歷了連續的斷裂-融合-橋接循環，從而產生了長度超過100兆鹼基的擴增子，並被夾在間期橋接中，然後碎裂，從而產生了微核，其微囊化的ecDNA是染色質碎裂的底物。
研究人員確定了與獲得性抗藥性或癌基因擴增相關的人類癌症中與局部基因擴增相關的相似基因組重排圖譜。研究人員認為，染色質碎裂是加速基因組DNA重排以及擴增為ecDNA的主要機制，並能夠快速獲得對變化生長條件的耐受性。
研究人員介紹，局部染色體擴增通過介導癌基因的過表達來促進癌症的發生，並通過增加其作用會降低抗癌藥功效的基因表達來促進癌症治療耐藥性的產生。
附：英文原文
Title: Chromothripsis drives the evolution of gene amplification in cancer
Author: Ofer Shoshani, Simon F. Brunner, Rona Yaeger, Peter Ly, Yael Nechemia-Arbely, Dong Hyun Kim, Rongxin Fang, Guillaume A. Castillon, Miao Yu, Julia S. Z. Li, Ying Sun, Mark H. Ellisman, Bing Ren, Peter J. Campbell, Don W. Cleveland
Issue&Volume: 2020-12-23
Abstract: Focal chromosomal amplification contributes to the initiation of cancer by mediating overexpression of oncogenes1,2,3, and to the development of cancer therapy resistance by increasing the expression of genes whose action diminishes the efficacy of anti-cancer drugs. Here we used whole-genome sequencing of clonal cell isolates that developed chemotherapeutic resistance to show that chromothripsis is a major driver of circular extrachromosomal DNA (ecDNA) amplification (also known as double minutes) through mechanisms that depend on poly(ADP-ribose) polymerases (PARP) and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). Longitudinal analyses revealed that a further increase in drug tolerance is achieved by structural evolution of ecDNAs through additional rounds of chromothripsis. In situ Hi-C sequencing showed that ecDNAs preferentially tether near chromosome ends, where they re-integrate when DNA damage is present. Intrachromosomal amplifications that formed initially under low-level drug selection underwent continuing breakage–fusion–bridge cycles, generating amplicons more than 100 megabases in length that became trapped within interphase bridges and then shattered, thereby producing micronuclei whose encapsulated ecDNAs are substrates for chromothripsis. We identified similar genome rearrangement profiles linked to localized gene amplification in human cancers with acquired drug resistance or oncogene amplifications. We propose that chromothripsis is a primary mechanism that accelerates genomic DNA rearrangement and amplification into ecDNA and enables rapid acquisition of tolerance to altered growth conditions.
DOI: 10.1038/s41586-020-03064-z
Source: https://www.nature.com/articles/s41586-020-03064-z