• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

RFWD3 和跨损伤 DNA 聚合酶有助于 PCNA 修饰依赖性的 DNA 损伤耐受。

RFWD3 and translesion DNA polymerases contribute to PCNA modification-dependent DNA damage tolerance.

机构信息

Department of Genome Dynamics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.

Department of Molecular Pharmaco-Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

出版信息

Life Sci Alliance. 2022 Jul 29;5(12):e202201584. doi: 10.26508/lsa.202201584.

DOI:10.26508/lsa.202201584
PMID:35905994
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9348633/
Abstract

DNA damage tolerance pathways are regulated by proliferating cell nuclear antigen (PCNA) modifications at lysine 164. Translesion DNA synthesis by DNA polymerase η (Polη) is well studied, but less is known about Polη-independent mechanisms. Illudin S and its derivatives induce alkyl DNA adducts, which are repaired by transcription-coupled nucleotide excision repair (TC-NER). We demonstrate that in addition to TC-NER, PCNA modification at K164 plays an essential role in cellular resistance to these compounds by overcoming replication blockages, with no requirement for Polη. Polκ and RING finger and WD repeat domain 3 (RFWD3) contribute to tolerance, and are both dependent on PCNA modifications. Although RFWD3 is a FANC protein, we demonstrate that it plays a role in DNA damage tolerance independent of the FANC pathway. Finally, we demonstrate that RFWD3-mediated cellular survival after UV irradiation is dependent on PCNA modifications but is independent of Polη. Thus, RFWD3 contributes to PCNA modification-dependent DNA damage tolerance in addition to translesion DNA polymerases.

摘要

DNA 损伤容忍途径受赖氨酸 164 上增殖细胞核抗原 (PCNA) 修饰的调节。DNA 聚合酶 η (Polη) 的跨损伤 DNA 合成研究得比较透彻，但对 Polη 不依赖的机制知之甚少。伊鲁毒素 S 及其衍生物诱导烷基 DNA 加合物，这些加合物通过转录偶联核苷酸切除修复 (TC-NER) 进行修复。我们证明，除了 TC-NER 之外，PCNA 在 K164 的修饰在克服复制阻断方面对细胞对这些化合物的抗性起着至关重要的作用，而不需要 Polη。Polκ 和环指和 WD 重复域 3 (RFWD3) 有助于耐受，两者都依赖于 PCNA 的修饰。尽管 RFWD3 是 FANC 蛋白，但我们证明它在 DNA 损伤容忍中发挥作用，而不依赖于 FANC 途径。最后，我们证明 RFWD3 介导的 UV 照射后细胞存活依赖于 PCNA 修饰，但不依赖于 Polη。因此，RFWD3 除了跨损伤 DNA 聚合酶外，还有助于 PCNA 修饰依赖性 DNA 损伤容忍。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ec4/9348633/585bc9533526/LSA-2022-01584_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ec4/9348633/ca0bf23b4366/LSA-2022-01584_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ec4/9348633/09dd454b2f8b/LSA-2022-01584_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ec4/9348633/7c04089ee9ed/LSA-2022-01584_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ec4/9348633/44ab7e275825/LSA-2022-01584_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ec4/9348633/4486e0904f83/LSA-2022-01584_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ec4/9348633/60b4259d6372/LSA-2022-01584_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ec4/9348633/e37fb751fd5e/LSA-2022-01584_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ec4/9348633/5457745df345/LSA-2022-01584_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ec4/9348633/7177a4e191d9/LSA-2022-01584_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ec4/9348633/e7cbed4b41b0/LSA-2022-01584_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ec4/9348633/585bc9533526/LSA-2022-01584_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ec4/9348633/ca0bf23b4366/LSA-2022-01584_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ec4/9348633/09dd454b2f8b/LSA-2022-01584_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ec4/9348633/7c04089ee9ed/LSA-2022-01584_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ec4/9348633/44ab7e275825/LSA-2022-01584_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ec4/9348633/4486e0904f83/LSA-2022-01584_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ec4/9348633/60b4259d6372/LSA-2022-01584_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ec4/9348633/e37fb751fd5e/LSA-2022-01584_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ec4/9348633/5457745df345/LSA-2022-01584_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ec4/9348633/7177a4e191d9/LSA-2022-01584_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ec4/9348633/e7cbed4b41b0/LSA-2022-01584_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ec4/9348633/585bc9533526/LSA-2022-01584_Fig6.jpg

相似文献

1
RFWD3 and translesion DNA polymerases contribute to PCNA modification-dependent DNA damage tolerance.RFWD3 和跨损伤 DNA 聚合酶有助于 PCNA 修饰依赖性的 DNA 损伤耐受。
Life Sci Alliance. 2022 Jul 29;5(12):e202201584. doi: 10.26508/lsa.202201584.
2
Relevance of simultaneous mono-ubiquitinations of multiple units of PCNA homo-trimers in DNA damage tolerance.增殖细胞核抗原同三聚体多个单元的同时单泛素化在DNA损伤耐受中的相关性
PLoS One. 2015 Feb 18;10(2):e0118775. doi: 10.1371/journal.pone.0118775. eCollection 2015.
3
DNA-damage tolerance mediated by PCNA*Ub fusions in human cells is dependent on Rev1 but not Polη.在人体细胞中，由 PCNA*Ub 融合介导的 DNA 损伤容忍依赖于 Rev1，但不依赖于 Polη。
Nucleic Acids Res. 2013 Aug;41(15):7356-69. doi: 10.1093/nar/gkt542. Epub 2013 Jun 12.
4
Structural basis for novel interactions between human translesion synthesis polymerases and proliferating cell nuclear antigen.人跨损伤合成聚合酶与增殖细胞核抗原之间新型相互作用的结构基础。
J Biol Chem. 2009 Apr 17;284(16):10552-60. doi: 10.1074/jbc.M809745200. Epub 2009 Feb 10.
5
PCNA ubiquitination-independent activation of polymerase η during somatic hypermutation and DNA damage tolerance.PCNA 泛素化非依赖性激活聚合酶 η 在体细胞超突变和 DNA 损伤耐受过程中的作用。
DNA Repair (Amst). 2011 Oct 10;10(10):1051-9. doi: 10.1016/j.dnarep.2011.08.005. Epub 2011 Sep 1.
6
Roles of PCNA ubiquitination and TLS polymerases κ and η in the bypass of methyl methanesulfonate-induced DNA damage.增殖细胞核抗原泛素化以及跨损伤合成聚合酶κ和η在甲磺酸甲酯诱导的DNA损伤跨越中的作用。
Nucleic Acids Res. 2015 Jan;43(1):282-94. doi: 10.1093/nar/gku1301. Epub 2014 Dec 10.
7
Requirement for functional DNA polymerase eta in genome-wide repair of UV-induced DNA damage during S phase.在 S 期，功能性 DNA 聚合酶 eta 在全基因组修复 UV 诱导的 DNA 损伤中的需求。
DNA Repair (Amst). 2010 Jul 1;9(7):754-64. doi: 10.1016/j.dnarep.2010.03.013. Epub 2010 Apr 24.
8
A genetic study based on PCNA-ubiquitin fusions reveals no requirement for PCNA polyubiquitylation in DNA damage tolerance.一项基于增殖细胞核抗原（PCNA）-泛素融合蛋白的遗传学研究表明，DNA损伤耐受并不需要PCNA多聚泛素化。
DNA Repair (Amst). 2017 Jun;54:46-54. doi: 10.1016/j.dnarep.2017.04.003. Epub 2017 Apr 14.
9
The Functions of Serine 687 Phosphorylation of Human DNA Polymerase η in UV Damage Tolerance.人DNA聚合酶η丝氨酸687磷酸化在紫外线损伤耐受中的作用
Mol Cell Proteomics. 2016 Jun;15(6):1913-20. doi: 10.1074/mcp.M115.052167. Epub 2016 Mar 17.
10
The ubiquitin-binding domain of DNA polymerase η directly binds to DNA clamp PCNA and regulates translesion DNA synthesis.DNA 聚合酶 η 的泛素结合域直接与 DNA 夹 PCNA 结合，调节跨损伤 DNA 合成。
J Biol Chem. 2022 Feb;298(2):101506. doi: 10.1016/j.jbc.2021.101506. Epub 2021 Dec 18.

引用本文的文献

1
Elucidating the genetic mechanisms governing cytosine base editing outcomes through CRISPRi screens.通过CRISPR干扰筛选阐明控制胞嘧啶碱基编辑结果的遗传机制。
Nat Commun. 2025 May 20;16(1):4685. doi: 10.1038/s41467-025-59948-z.
2
Estrogen Promotes Endometrial Cancer Development by Modulating ZNF626, SLK, and RFWD3 Gene Expression and Inducing Immune Inflammatory Changes.雌激素通过调节ZNF626、SLK和RFWD3基因表达并诱导免疫炎症变化促进子宫内膜癌发展。
Biomedicines. 2025 Feb 17;13(2):498. doi: 10.3390/biomedicines13020498.
3
E3 ligases: a ubiquitous link between DNA repair, DNA replication and human disease.

本文引用的文献

1
The ubiquitin ligase RFWD3 is required for translesion DNA synthesis.泛素连接酶 RFWD3 是跨损伤 DNA 合成所必需的。
Mol Cell. 2021 Feb 4;81(3):442-458.e9. doi: 10.1016/j.molcel.2020.11.029. Epub 2020 Dec 14.
2
A Genetic Map of the Response to DNA Damage in Human Cells.人类细胞对 DNA 损伤反应的遗传图谱。
Cell. 2020 Jul 23;182(2):481-496.e21. doi: 10.1016/j.cell.2020.05.040. Epub 2020 Jul 9.
3
DNA damage tolerance in stem cells, ageing, mutagenesis, disease and cancer therapy.干细胞中的 DNA 损伤容忍、衰老、突变、疾病和癌症治疗。
E3 连接酶：DNA 修复、复制与人类疾病之间普遍存在的联系。
Biochem J. 2024 Jul 17;481(14):923-944. doi: 10.1042/BCJ20240124.
4
SMARCAL1 ubiquitylation controls its association with RPA-coated ssDNA and promotes replication fork stability.SMARCAL1 的泛素化控制其与 RPA 包被的单链 DNA 的结合，并促进复制叉的稳定性。
PLoS Biol. 2024 Mar 19;22(3):e3002552. doi: 10.1371/journal.pbio.3002552. eCollection 2024 Mar.
5
RFWD3 promotes ZRANB3 recruitment to regulate the remodeling of stalled replication forks.RFWD3 促进 ZRANB3 的募集，以调节停滞复制叉的重塑。
J Cell Biol. 2023 May 1;222(5). doi: 10.1083/jcb.202106022. Epub 2023 Apr 10.
6
Novel mechanisms for the removal of strong replication-blocking HMCES- and thiazolidine-DNA adducts in humans.新型机制可去除人源中具有强复制阻断作用的 HMCES 和噻唑烷-DNA 加合物。
Nucleic Acids Res. 2023 Jun 9;51(10):4959-4981. doi: 10.1093/nar/gkad246.
Nucleic Acids Res. 2019 Aug 22;47(14):7163-7181. doi: 10.1093/nar/gkz531.
4
Mechanisms of DNA Damage Tolerance: Post-Translational Regulation of PCNA.DNA损伤耐受机制：增殖细胞核抗原的翻译后调控
Genes (Basel). 2018 Dec 24;10(1):10. doi: 10.3390/genes10010010.
5
Regulation of HLTF-mediated PCNA polyubiquitination by RFC and PCNA monoubiquitination levels determines choice of damage tolerance pathway.HLTF 介导的 PCNA 多泛素化受 RFC 和 PCNA 单泛素化水平的调节，决定了损伤耐受途径的选择。
Nucleic Acids Res. 2018 Nov 30;46(21):11340-11356. doi: 10.1093/nar/gky943.
6
Eukaryotic translesion synthesis: Choosing the right tool for the job.真核生物跨损伤合成：为工作选择合适的工具。
DNA Repair (Amst). 2018 Nov;71:127-134. doi: 10.1016/j.dnarep.2018.08.016. Epub 2018 Aug 24.
7
Mechanism of RNA polymerase II stalling by DNA alkylation.DNA 烷化作用导致 RNA 聚合酶 II 暂停的机制。
Proc Natl Acad Sci U S A. 2017 Nov 14;114(46):12172-12177. doi: 10.1073/pnas.1706592114. Epub 2017 Oct 30.
8
Replication Fork Slowing and Reversal upon DNA Damage Require PCNA Polyubiquitination and ZRANB3 DNA Translocase Activity.DNA损伤时复制叉的减速与逆转需要PCNA多聚泛素化及ZRANB3 DNA转位酶活性。
Mol Cell. 2017 Sep 7;67(5):882-890.e5. doi: 10.1016/j.molcel.2017.08.010.
9
Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia.泛素连接酶RFWD3的双等位基因突变会导致范可尼贫血。
J Clin Invest. 2017 Aug 1;127(8):3013-3027. doi: 10.1172/JCI92069. Epub 2017 Jul 10.
10
Regulation of DNA damage tolerance in mammalian cells by post-translational modifications of PCNA.通过增殖细胞核抗原的翻译后修饰对哺乳动物细胞中DNA损伤耐受性的调控。
Mutat Res. 2017 Oct;803-805:82-88. doi: 10.1016/j.mrfmmm.2017.06.004. Epub 2017 Jun 21.