更新于：2024-09-19

RNF168

更新于：2024-09-19

基本信息

别名

E3 ubiquitin-protein ligase RNF168、FLJ35794、hRNF168

+ [3]

简介

E3 ubiquitin-protein ligase required for accumulation of repair proteins to sites of DNA damage. Acts with UBE2N/UBC13 to amplify the RNF8-dependent histone ubiquitination. Recruited to sites of DNA damage at double-strand breaks (DSBs) by binding to ubiquitinated histone H2A and H2AX and amplifies the RNF8-dependent H2A ubiquitination, promoting the formation of 'Lys-63'-linked ubiquitin conjugates. This leads to concentrate ubiquitinated histones H2A and H2AX at DNA lesions to the threshold required for recruitment of TP53BP1 and BRCA1. Also recruited at DNA interstrand cross-links (ICLs) sites and promotes accumulation of 'Lys-63'-linked ubiquitination of histones H2A and H2AX, leading to recruitment of FAAP20/C1orf86 and Fanconi anemia (FA) complex, followed by interstrand cross-link repair. H2A ubiquitination also mediates the ATM-dependent transcriptional silencing at regions flanking DSBs in cis, a mechanism to avoid collision between transcription and repair intermediates. Also involved in class switch recombination in immune system, via its role in regulation of DSBs repair. Following DNA damage, promotes the ubiquitination and degradation of JMJD2A/KDM4A in collaboration with RNF8, leading to unmask H4K20me2 mark and promote the recruitment of TP53BP1 at DNA damage sites. Not able to initiate 'Lys-63'-linked ubiquitination in vitro; possibly due to partial occlusion of the UBE2N/UBC13-binding region. Catalyzes monoubiquitination of 'Lys-13' and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub, respectively).

关联

100 项与 RNF168 相关的临床结果

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100 项与 RNF168 相关的转化医学

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0 项与 RNF168 相关的专利（医药）

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236

项与 RNF168 相关的文献（医药）

2024-09-01·Life Sciences

RNF8-mediated multi-ubiquitination of MCM7: Linking disassembly of the CMG helicase with DNA damage response in human cells

Article

作者: Luo, Jing ; Fu, Zhisong ; Sun, Qianqian ; Zhao, Wenhui ; Li, Shirui ; Sui, Yaqi ; Zhou, Rui

DNA damage causes genomic instability. To maintain genome integrity, cells have evolved DNA damage response, which is involved in replication fork disassembly and DNA replication termination. However, the mechanism underlying the regulation of replication fork disassembly and its connection with DNA damage repair remain elusive. The CMG-MCM7 subunit ubiquitination functions on the eukaryotic replication fork disassembly at replication termination. Until now, only ubiquitin ligases CUL2^LRR1 have been reported catalyzing MCM7 ubiquitination in human cells. This study discovered that in human cells, the ubiquitin ligase RNF8 catalyzes K63-linked multi-ubiquitination of MCM7 at K145 both in vivo and in vitro. The multi-ubiquitination of MCM7 is dynamically regulated during the cell cycle, primarily presenting on chromatin during the late S phase. Additionally, MCM7 polyubiquitylation is promoted by RNF168 and BRCA1 during DNA replication termination. Upon DNA damage, the RNF8-mediated polyubiquitination of MCM7 decreased significantly during the late S phase. This study highlights the novel role of RNF8-catalyzed polyubiquitination of MCM7 in the regulation of replication fork disassembly in human cells and linking it to DNA damage response.

2024-08-27·Nucleic Acids Research

A RAD18–UBC13–PALB2–RNF168 axis mediates replication fork recovery in BRCA1-deficient cancer cells

Article

作者: Lemacon, Delphine ; Limbu, Mangsi ; Zou, Lee ; Tirman, Stephanie ; Cybulla, Emily ; Quinet, Annabel ; Fuh, Katherine ; Meroni, Alice ; Lomonosova, Elena ; Tennakoon, Mithila ; Noia, Hollie ; Vindigni, Alessandro ; Wallace, Sierra ; Wood, Matthew ; Jackson, Jessica ; Agashe, Sumedha

AbstractBRCA1/2 proteins function in genome stability by promoting repair of double-stranded DNA breaks through homologous recombination and by protecting stalled replication forks from nucleolytic degradation. In BRCA1/2-deficient cancer cells, extensively degraded replication forks can be rescued through distinct fork recovery mechanisms that also promote cell survival. Here, we identified a novel pathway mediated by the E3 ubiquitin ligase RAD18, the E2-conjugating enzyme UBC13, the recombination factor PALB2, the E3 ubiquitin ligase RNF168 and PCNA ubiquitination that promotes fork recovery in BRCA1- but not BRCA2-deficient cells. We show that this pathway does not promote fork recovery by preventing replication fork reversal and degradation in BRCA1-deficient cells. We propose a mechanism whereby the RAD18–UBC13–PALB2–RNF168 axis facilitates resumption of DNA synthesis by promoting re-annealing of the complementary single-stranded template strands of the extensively degraded forks, thereby allowing re-establishment of a functional replication fork. We also provide preliminary evidence for the potential clinical relevance of this novel fork recovery pathway in BRCA1-mutated cancers, as RAD18 is over-expressed in BRCA1-deficient cancers, and RAD18 loss compromises cell viability in BRCA1-deficient cancer cells.

2024-07-17·Biochemical Journal

E3 ligases: a ubiquitous link between DNA repair, DNA replication and human disease

Review

作者: Stewart, Grant S. ; Jhujh, Satpal S. ; Chauhan, Anoop S.

Maintenance of genome stability is of paramount importance for the survival of an organism. However, genomic integrity is constantly being challenged by various endogenous and exogenous processes that damage DNA. Therefore, cells are heavily reliant on DNA repair pathways that have evolved to deal with every type of genotoxic insult that threatens to compromise genome stability. Notably, inherited mutations in genes encoding proteins involved in these protective pathways trigger the onset of disease that is driven by chromosome instability e.g. neurodevelopmental abnormalities, neurodegeneration, premature ageing, immunodeficiency and cancer development. The ability of cells to regulate the recruitment of specific DNA repair proteins to sites of DNA damage is extremely complex but is primarily mediated by protein post-translational modifications (PTMs). Ubiquitylation is one such PTM, which controls genome stability by regulating protein localisation, protein turnover, protein-protein interactions and intra-cellular signalling. Over the past two decades, numerous ubiquitin (Ub) E3 ligases have been identified to play a crucial role not only in the initiation of DNA replication and DNA damage repair but also in the efficient termination of these processes. In this review, we discuss our current understanding of how different Ub E3 ligases (RNF168, TRAIP, HUWE1, TRIP12, FANCL, BRCA1, RFWD3) function to regulate DNA repair and replication and the pathological consequences arising from inheriting deleterious mutations that compromise the Ub-dependent DNA damage response.

项与 RNF168 相关的新闻（医药）

2023-08-30

·生物谷

Cancer Research | 郑晓峰揭示SUMO化修饰通过调控液-液相分离来影响NHEJ修复效率和肿瘤细胞耐药的分子机制

近日，Cancer Research期刊在线发表了北京大学生命科学学院郑晓峰研究组的题为“SENP1 decreases RNF168 phase separation to promote DNA damage repair and drug resistance in colon cancer”的研究文章。该研究发现去SUMO化酶SENP1应答DNA双链断裂损伤被招募到损伤位点，通过去除RNF168的SUMO化修饰来破坏其诱导的RNF168液-液相分离，进而促进非同源末端连接修复，证实SENP1在结肠癌细胞中高表达，促进癌细胞对化疗药物的耐受。该研究揭示了SUMO化修饰通过影响液-液相分离调控DNA损伤修复效率及肿瘤细胞耐药的分子机制。DNA作为遗传信息的主要载体，其结构的完整与功能的完善对于维持基因组的稳定性和保障生命体正常生理活动具有重要意义。不同类型的DNA损伤修复对于维持基因组稳定性至关重要，针对最严重的DNA双链断裂损伤（DSB），细胞主要通过非同源末端连接修复（NHEJ）与同源末端重组修复（HR）进行修复。泛素E3连接酶RNF168是DNA双链断裂损伤修复通路中早期响应损伤的修复蛋白。已有的研究表明，蛋白质翻译后修饰在双链断裂修复中发挥重要的调控作用，但是RNF168的翻译后修饰在其功能中的调控作用有待于揭示。该研究发现RNF168的SUMO化修饰促进其在细胞核内液-液相分离（LLPS）的形成，阻碍RNF168被招募到DNA损伤位点，进而下调RNF168对组蛋白H2A的泛素化修饰。同时，该LLPS液滴包裹下游关键修复蛋白53BP1，抑制其被招募到损伤修复位点并最终导致NHEJ修复效率的下降。进一步研究表明，SENP1是RNF168的特异性去SUMO化酶。当DNA双链断裂损伤发生时，结肠癌细胞中高表达的SENP1去除RNF168的SUMO化修饰，阻止RNF168液－液相分离形成，从而维持基因组的稳定性，使肿瘤细胞对化疗药物产生抵抗，最终导致肿瘤进一步恶化，肿瘤组织中SENP1的高水平表达与癌症患者预后不良相关。SENP1调控DNA损伤修复模式图该研究利用癌细胞和小鼠模型，揭示了RNF168 SUMO化修饰通过液-液相分离调控DNA损伤应答的分子机制，证明SENP1-RNF168-53BP1信号轴在肿瘤细胞的化疗耐药性中发挥重要调控作用，提示抑制SENP1是一种潜在的结肠癌治疗策略。会议推荐会议详情会议名称：2023（第14届）细胞与基因治疗研讨会暨抗体工程与创新免疫治疗技术论坛主办单位：生物谷、梅斯医学、同济大学附属同济医院、南京可缘大会时间：9月22-23日大会地点：上海大会规模：1500人2010年至今，生物谷联合各合作单位已经顺利召开了13届细胞与基因治疗研讨会，与全球致力于细胞治疗行业同仁们一同成长沉淀，在提供行业信息交流平台的同时，也为基础研究提供了技术/产品等产业化的孵化平台。基于此，本届会议将继续以转化医学为切入点，以基础研究与临床应用相结合，针对细胞治疗的临床前沿研究、临床监管、治疗规范、细胞治疗安全性，免疫细胞新型疗法、实体瘤治疗、干细胞与癌症、抗体药物、核酸药物、基因编辑、肿瘤免疫治疗等热门议题进行讨论，诚邀国内外产学研医专家共聚，共绘产业发展新蓝图！长按识别二维码立即报名参会

细胞疗法免疫疗法核酸药物

2023-08-02

·生物谷

研究揭示SUMO化修饰通过调控液-液相分离来影响NHEJ修复效率和肿瘤细胞耐药的分子机制

该研究发现RNF168的SUMO化修饰促进其在细胞核内液-液相分离（LLPS）的形成，阻碍RNF168被招募到DNA损伤位点，进而下调RNF168对组蛋白H2A的泛素化修饰。近日，Cancer Research期刊在线发表了北京大学生命科学学院郑晓峰研究组的题为“SENP1 decreases RNF168 phase separation to promote DNA damage repair and drug resistance in colon cancer”的研究文章。该研究发现去SUMO化酶SENP1应答DNA双链断裂损伤被招募到损伤位点，通过去除RNF168的SUMO化修饰来破坏其诱导的RNF168液-液相分离，进而促进非同源末端连接修复，证实SENP1在结肠癌细胞中高表达，促进癌细胞对化疗药物的耐受。该研究揭示了SUMO化修饰通过影响液-液相分离调控DNA损伤修复效率及肿瘤细胞耐药的分子机制。 DNA作为遗传信息的主要载体，其结构的完整与功能的完善对于维持基因组的稳定性和保障生命体正常生理活动具有重要意义。不同类型的DNA损伤修复对于维持基因组稳定性至关重要，针对最严重的DNA双链断裂损伤（DSB），细胞主要通过非同源末端连接修复（NHEJ）与同源末端重组修复（HR）进行修复。泛素E3连接酶RNF168是DNA双链断裂损伤修复通路中早期响应损伤的修复蛋白。已有的研究表明，蛋白质翻译后修饰在双链断裂修复中发挥重要的调控作用，但是RNF168的翻译后修饰在其功能中的调控作用有待于揭示。该研究发现RNF168的SUMO化修饰促进其在细胞核内液-液相分离（LLPS）的形成，阻碍RNF168被招募到DNA损伤位点，进而下调RNF168对组蛋白H2A的泛素化修饰。同时，该LLPS液滴包裹下游关键修复蛋白53BP1，抑制其被招募到损伤修复位点并最终导致NHEJ修复效率的下降。进一步研究表明，SENP1是RNF168的特异性去SUMO化酶。当DNA双链断裂损伤发生时，结肠癌细胞中高表达的SENP1去除RNF168的SUMO化修饰，阻止RNF168液－液相分离形成，从而维持基因组的稳定性，使肿瘤细胞对化疗药物产生抵抗，最终导致肿瘤进一步恶化，肿瘤组织中SENP1的高水平表达与癌症患者预后不良相关。 SENP1调控DNA损伤修复模式图该研究利用癌细胞和小鼠模型，揭示了RNF168 SUMO化修饰通过液-液相分离调控DNA损伤应答的分子机制，证明SENP1-RNF168-53BP1信号轴在肿瘤细胞的化疗耐药性中发挥重要调控作用，提示抑制SENP1是一种潜在的结肠癌治疗策略。郑晓峰课题组的博士研究生卫敏为文章的第一作者，黄新平、廖礼铭也在该论文中作出了重要贡献。郑晓峰为文章的通讯作者。该研究得到了国家自然科学基金重点项目、蛋白质与植物基因研究国家重点实验室、生命科学学院、生命科学学院仪器中心以及凤凰平台的大力支持。

细胞疗法临床申请核酸药物

2023-07-05

·生物谷

Cancer Res：郑晓峰团队揭示SUMO化修饰通过调控相分离影响DNA修复和肿瘤耐药的机制

DNA作为遗传信息的主要载体，其结构的完整与功能的完善对于维持基因组的稳定性和保障生命体正常生理活动具有重要意义。不同类型的DNA损伤修复对于维持基因组稳定性至关重要，针对最严重的DNA双链断裂损伤 DNA作为遗传信息的主要载体，其结构的完整与功能的完善对于维持基因组的稳定性和保障生命体正常生理活动具有重要意义。不同类型的DNA损伤修复对于维持基因组稳定性至关重要，针对最严重的DNA双链断裂损伤（DSB），细胞主要通过非同源末端连接（NHEJ）与同源末端重组（HR）进行修复。泛素E3连接酶RNF168是DNA双链断裂损伤修复通路中早期响应损伤的修复蛋白。已有的研究表明，蛋白质翻译后修饰在双链断裂修复中发挥重要的调控作用，但是RNF168的翻译后修饰在其功能中的调控作用有待于揭示。近日，北京大学郑晓峰课题组在 Cancer Research 期刊发表了题为：SENP1 decreases RNF168 phase separation to promote DNA damage repair and drug resistance in colon cancer 的研究论文。该研究发现，去SUMO化酶SENP1应答DNA双链断裂损伤被招募到损伤位点，通过去除RNF168的SUMO化修饰来破坏其诱导的RNF168的液-液相分离（LLPS），进而促进非同源末端连接（NHEJ）修复，证实SENP1在结肠癌细胞中高表达，促进癌细胞对化疗药物的耐受。该研究揭示了SUMO化修饰通过影响液-液相分离调控DNA损伤修复效率及肿瘤细胞耐药的分子机制。该研究发现RNF168的SUMO化修饰促进其在细胞核内液-液相分离（LLPS）的形成，阻碍RNF168被招募到DNA损伤位点，进而下调RNF168对组蛋白H2A的泛素化修饰。同时，该LLPS液滴包裹下游关键修复蛋白53BP1，抑制其被招募到损伤修复位点并最终导致NHEJ修复效率的下降。进一步研究表明，SENP1是RNF168的特异性去SUMO化酶。当DNA双链断裂损伤发生时，结肠癌细胞中高表达的SENP1去除RNF168的SUMO化修饰，阻止RNF168液－液相分离形成，从而维持基因组的稳定性，使肿瘤细胞对化疗药物产生抵抗，最终导致肿瘤进一步恶化，肿瘤组织中SENP1的高水平表达与癌症患者预后不良相关。该研究利用癌细胞和小鼠模型，揭示了RNF168 SUMO化修饰通过液-液相分离调控DNA损伤应答的分子机制，证明SENP1-RNF168-53BP1信号轴在肿瘤细胞的化疗耐药性中发挥重要调控作用，提示抑制SENP1是一种潜在的结肠癌治疗策略。北京大学郑晓峰课题组的博士研究生卫敏为论文第一作者，黄新平、廖礼铭也在该论文中做出了重要贡献。郑晓峰教授为文章的通讯作者。该研究得到了国家自然科学基金重点项目、蛋白质与植物基因研究国家重点实验室、生命科学学院、生命科学学院仪器中心以及凤凰平台的大力支持。