Radiotherapy is widely used in the management of advanced colorectal cancer(CRC).However,the clinical efficacy is limited by the safe irradiated dose.Sensitizing tumor cells to radiotherapy via interrupting DNA repair...Radiotherapy is widely used in the management of advanced colorectal cancer(CRC).However,the clinical efficacy is limited by the safe irradiated dose.Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation.The BRCA1-BARD1 complex has been demonstrated to play a critical role in homologous recombination(HR)DSB repair,and its functions may be affected by HERC2 or BAP1.Accumulated evidence illustrates that the ubiquitination-deubiquitination balance is involved in these processes;however,the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn’t been defined.Through activity-based profiling,we identified PT33 as an active entity for HR repair suppression.Subsequently,we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen.Mechanistically,pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction,interrupting HR repair.Consequently,PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo.Overall,these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.展开更多
目的:探讨HERC2基因变异所致智力障碍伴发育迟缓1个家系的遗传学特征。方法:选取于2020年5—7月在大理大学第一附属医院就诊的1个智力障碍伴发育迟缓的患儿家系3代共10人为研究对象。收集该家系先证者的临床资料及家系成员患病情况,应...目的:探讨HERC2基因变异所致智力障碍伴发育迟缓1个家系的遗传学特征。方法:选取于2020年5—7月在大理大学第一附属医院就诊的1个智力障碍伴发育迟缓的患儿家系3代共10人为研究对象。收集该家系先证者的临床资料及家系成员患病情况,应用全外显子组测序技术对先证者进行致病基因筛选,采用Sanger测序对可疑致病基因进行家系验证。根据美国遗传学与基因组学(American College of Medical Genetics and Genomics,ACMG)学会的基因变异解读标准与指南对可疑致病基因突变位点进行致病性分类。结果:先证者男,12岁,因“发育迟缓9年,智力障碍3个月”就诊,表现为身材矮小,无故自语自笑,眼神对周围环境回避,韦氏智力测验提示智力水平低下。先证者弟弟有类似智力障碍伴发育迟缓等表现,余家系成员正常。全外显子组测序结果显示先证者携带HERC2基因c.7675A>G位点纯合突变,Sanger测序显示其弟弟携带同样的HERC2基因c.7675A>G位点纯合突变,其余家系成员携带相同的HERC2基因c.7675A>G位点杂合突变。根据ACMG指南判定该基因位点突变为临床意义未明。结论:HERC2基因c.7675A>G位点突变可能是导致该家系智力障碍伴发育迟缓的遗传学基础。展开更多
基金supported by the National Natural Science Foundation of China(NSFC)(No.82272743 to Xin Yue(82172812)of NSFC to Ran-yi Liu+4 种基金81871996 to Ran-yi Liu82003218 to Xuecen Wang82072029 to Zhenwei Peng and 81973174 to Xianzhang Bu)Guangdong Basic and Applied Basic Research Foundation(No.2021A1515012496 to Xin Yue and 2022A1515012221 to Xianzhang Bu)Basic Scientific Research Operation of Sun Yat-sen University(No.19ykpy192 to Xin Yue)。
文摘Radiotherapy is widely used in the management of advanced colorectal cancer(CRC).However,the clinical efficacy is limited by the safe irradiated dose.Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation.The BRCA1-BARD1 complex has been demonstrated to play a critical role in homologous recombination(HR)DSB repair,and its functions may be affected by HERC2 or BAP1.Accumulated evidence illustrates that the ubiquitination-deubiquitination balance is involved in these processes;however,the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn’t been defined.Through activity-based profiling,we identified PT33 as an active entity for HR repair suppression.Subsequently,we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen.Mechanistically,pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction,interrupting HR repair.Consequently,PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo.Overall,these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.
文摘目的:探讨HERC2基因变异所致智力障碍伴发育迟缓1个家系的遗传学特征。方法:选取于2020年5—7月在大理大学第一附属医院就诊的1个智力障碍伴发育迟缓的患儿家系3代共10人为研究对象。收集该家系先证者的临床资料及家系成员患病情况,应用全外显子组测序技术对先证者进行致病基因筛选,采用Sanger测序对可疑致病基因进行家系验证。根据美国遗传学与基因组学(American College of Medical Genetics and Genomics,ACMG)学会的基因变异解读标准与指南对可疑致病基因突变位点进行致病性分类。结果:先证者男,12岁,因“发育迟缓9年,智力障碍3个月”就诊,表现为身材矮小,无故自语自笑,眼神对周围环境回避,韦氏智力测验提示智力水平低下。先证者弟弟有类似智力障碍伴发育迟缓等表现,余家系成员正常。全外显子组测序结果显示先证者携带HERC2基因c.7675A>G位点纯合突变,Sanger测序显示其弟弟携带同样的HERC2基因c.7675A>G位点纯合突变,其余家系成员携带相同的HERC2基因c.7675A>G位点杂合突变。根据ACMG指南判定该基因位点突变为临床意义未明。结论:HERC2基因c.7675A>G位点突变可能是导致该家系智力障碍伴发育迟缓的遗传学基础。
