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《自然》:染色体碎裂促进癌症中基因扩增的进化 促癌 耐药

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《自然》:染色体碎裂促进癌症中基因扩增的进化   

染色体局部扩增通过介导致癌基因过度表达诱导癌症发生以及癌症疗法抗性。本研究对发展出化疗抗性的克隆细胞分离株进行全基因组测序,发现染色体碎裂是染色体外环状DNA(ecDNA)扩增的驱动因素,主要通过聚(ADP-核糖)聚合酶(PARP)和DNA依赖性蛋白激酶(DNA-PKcs)催化亚基发挥作用。因此,染色体碎裂加速DNA基因组重排,扩增成ecDNA,并且面对不断变化的生长条件形成一定抗性。癌症发病机理、化学治疗学、抗癌药耐药等关联的基础医学研究论文。

(染色质碎裂是加速基因组DNA重排以及扩增为ecDNA  癌基因的过表达  降低抗癌药功效的基因表达来促进癌症治疗耐药性的产生。癌症发病机理、化学治疗学、抗癌药耐药等关联的基础医学研究论文。)

(染色质碎裂是加速基因组DNA重排以及扩增为ecDNA的主要机制,并能够快速获得对变化生长条件的耐受性。
局部染色体扩增通过介导癌基因的过表达来促进癌症的发生,并通过增加其作用会降低抗癌药功效的基因表达来促进癌症治疗耐药性的产生。)

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。

研究人员对产生化学治疗抗性的克隆细胞分离株进行了全基因组测序,结果表明,通过依赖于聚(ADP-核糖)聚合酶(PARP)和DNA依赖性蛋白激酶(DNA-PKcs)催化亚基的机制,染色体碎裂是环状染色体外DNA(ecDNA)扩增的主要驱动力 。

纵向分析显示,通过另外几轮染色体碎裂,ecDNA的结构进化进一步提高了药物耐受性。原位Hi-C测序表明,ecDNA优先束缚在染色体末端附近,当存在DNA损伤时它们会重新整合。最初在低水平药物选择下形成的染色体内扩增经历了连续的断裂-融合-桥接循环,从而产生了长度超过100兆碱基的扩增子,并被夹在间期桥接中,然后碎裂,从而产生了微核,其微囊化的ecDNA是染色质碎裂的底物。

研究人员确定了与获得性抗药性或癌基因扩增相关的人类癌症中与局部基因扩增相关的相似基因组重排图谱。研究人员认为,染色质碎裂是加速基因组DNA重排以及扩增为ecDNA的主要机制,并能够快速获得对变化生长条件的耐受性。

研究人员介绍,局部染色体扩增通过介导癌基因的过表达来促进癌症的发生,并通过增加其作用会降低抗癌药功效的基因表达来促进癌症治疗耐药性的产生。

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

期刊信息
Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html

http://news.sciencenet.cn/htmlpa ... 51253469760413.shtm



Nature:染色体碎裂驱动癌症中基因扩增的发展

领研网

2021/03/14

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.

所属学科:
医学
(导读 阿金)染色体局部扩增通过介导致癌基因过度表达诱导癌症发生以及癌症疗法抗性。本研究对发展出化疗抗性的克隆细胞分离株进行全基因组测序,发现染色体碎裂是染色体外环状DNA(ecDNA)扩增的驱动因素,主要通过聚(ADP-核糖)聚合酶(PARP)和DNA依赖性蛋白激酶(DNA-PKcs)催化亚基发挥作用。因此,染色体碎裂加速DNA基因组重排,扩增成ecDNA,并且面对不断变化的生长条件形成一定抗性。

文章标签
肿瘤基因组学
染色体
癌症疗法抗性
肿瘤生成

https://www.nature.com/articles/s41586-020-03064-z

https://www.linkresearcher.com/t ... c-8bab-829546dbdae6



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