作者：小柯机器人 发布时间：2020/12/25 12:53:46
本期文章：《自然》：Online/在线发表
美国加州大学圣地亚哥分校Don W. Cleveland、Peter J. Campbell等研究人员合作发现，染色体碎裂可促进癌症中基因扩增的进化。2020年12月23日，《自然》杂志在线发表了这项成果。
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.
论文
论文标题：Chromothripsis drives the evolution of gene amplification in cancer
作者：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
期刊：Nature
发表时间：2020/12/23
数字识别码：10.1038/s41586-020-03064-z
摘要：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.
