DNA-PK激酶复合体调节肿瘤疱疹病毒KSHV复制的分子机制
结题报告
批准号:
31970156
项目类别:
面上项目
资助金额:
58.0 万元
负责人:
张军杰
依托单位:
学科分类:
病毒学
结题年份:
2023
批准年份:
2019
项目状态:
已结题
项目参与者:
张军杰
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中文摘要
癌症是人类健康的最大威胁之一,约20%的癌症与病毒感染直接相关。卡波氏肉瘤相关疱疹病毒KSHV是一种重要的肿瘤疱疹病毒,其感染可引起多种恶性肿瘤。KSHV感染细胞后形成潜伏感染,在特定刺激下,进行裂解性复制。已有研究表明KSHV潜伏感染及裂解性复制在肿瘤发生中均发挥了重要作用,但KSHV不同感染周期的调控机制尚不清楚。我们通过CRISPR-Cas9系统筛选发现激酶复合体DNA-PK在KSHV裂解复制中发挥重要作用。进一步研究发现DNA-PK对KSHV形成潜伏感染也是必须的,而在KSHV裂解性复制时,抑制DNA-PK激酶活性则可以显著提高KSHV病毒复制水平。因此,DNA-PK在KSHV的潜伏感染和裂解复制中均发挥了关键作用。我们计划研究DNA-PK复合体调控KSHV潜伏感染和裂解复制的分子机制,探索DNA-PK特异抑制剂是否有助于清除KSHV潜伏感染,抑制恶性肿瘤的发生。
英文摘要
Virus infection contributes significantly to the development of human cancers and it is estimated that about 20% of human cancers are linked to infection. Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV) is one of seven human oncoviruses, whose infection can cause cancer. KSHV is the etiological agent for KS and is also associated with primary effusion lymphoma and multicentric Castleman’s disease. The life cycle of KSHV consists of two phases, latent infection and lytic replication, and both phases contributes to viral oncogenesis including the development of Kaposi’s sarcoma (KS). However, the molecular mechanism controlling latent infection and lytic replication is not well understood. We applied genome-wide CRISPR-Cas9 screening to identify cellular factors that regulates latent/lytic infection of KSHV and found DNA-PK plays critical roles in both latent infection and lytic replication. Our preliminary data indicate that DNA-PK is necessary for the establishment of latent infection after de novo infection, while its activation hampers viral lytic replication. We plan to further investigate how DNA-PK regulates KSHV replication and examine whether DNA-PK specific inhibitors are effective in eliminating KSHV latent infection and treating KS and the other related malignancies.
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专利列表
DOI:10.1038/s41556-023-01185-x
发表时间:2023-07
期刊:Nature Cell Biology
影响因子:21.3
作者:Liting Zhang;Congqing Jiang;Yunhong Zhong;Kongliang Sun;Huiru Jing;Jiayu Song;Jun Xie;Yaru Zhou;Mao Tian;Chuchu Zhang;Xiaona Sun;Shaowei Wang;Xi Cheng;Yuelan Zhang;Wei Wei-Wei;Xiang Li;Bishi Fu;P. Feng;Bing Wu;H. Shu;Junjie Zhang
通讯作者:Liting Zhang;Congqing Jiang;Yunhong Zhong;Kongliang Sun;Huiru Jing;Jiayu Song;Jun Xie;Yaru Zhou;Mao Tian;Chuchu Zhang;Xiaona Sun;Shaowei Wang;Xi Cheng;Yuelan Zhang;Wei Wei-Wei;Xiang Li;Bishi Fu;P. Feng;Bing Wu;H. Shu;Junjie Zhang
DOI:10.1016/j.omto.2023.04.006
发表时间:2023-06-15
期刊:MOLECULAR THERAPY ONCOLYTICS
影响因子:--
作者:Xie, Jun;Wang, Shaowei;Zhong, Yunhong;Gao, Ming;Tian, Xuezhang;Zhang, Liting;Pan, Dongli;Qin, Qingsong;Wu, Bing;Lan, Ke;Sun, Zhi-Jun;Zhang, Junjie
通讯作者:Zhang, Junjie
DOI:10.1128/mbio.00549-23
发表时间:2023-04-25
期刊:mBio
影响因子:6.4
作者:
通讯作者:
DOI:10.1038/s41467-020-19941-0
发表时间:2020-12-03
期刊:Nature communications
影响因子:16.6
作者:Sun X;Liu T;Zhao J;Xia H;Xie J;Guo Y;Zhong L;Li M;Yang Q;Peng C;Rouvet I;Belot A;Shu HB;Feng P;Zhang J
通讯作者:Zhang J
卡波氏肉瘤相关疱疹病毒劫持OTUD4-USP7(HAUSP)去泛素化酶促进裂解再激活的机制研究
  • 批准号:
    82372241
  • 项目类别:
    面上项目
  • 资助金额:
    49万元
  • 批准年份:
    2023
  • 负责人:
    张军杰
  • 依托单位:
全基因组CIRSPR-Cas9筛选发现SMCHD1限制疱疹病毒复制
  • 批准号:
    82172261
  • 项目类别:
    面上项目
  • 资助金额:
    55万元
  • 批准年份:
    2021
  • 负责人:
    张军杰
  • 依托单位:
国内基金
海外基金