• 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

APLF 促进链间 DNA 交联修复和复制叉保护，从而赋予顺铂耐药性。

APLF facilitates interstrand DNA crosslink repair and replication fork protection to confer cisplatin resistance.

机构信息

Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 35, Xiao-Tong Road, Tainan 704, Taiwan.

Department of Life Sciences, National Cheng Kung University, No. 1 University Road, Tainan City701, Taiwan.

出版信息

Nucleic Acids Res. 2024 Jun 10;52(10):5676-5697. doi: 10.1093/nar/gkae211.

DOI:10.1093/nar/gkae211
PMID:38520407
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11162786/
Abstract

Replication stress converts the stalled forks into reversed forks, which is an important protection mechanism to prevent fork degradation and collapse into poisonous DNA double-strand breaks (DSBs). Paradoxically, the mechanism also acts in cancer cells to contribute to chemoresistance against various DNA-damaging agents. PARP1 binds to and is activated by stalled forks to facilitate fork reversal. Aprataxin and polynucleotide kinase/phosphatase-like factor (APLF) binds to PARP1 through the poly(ADP-ribose) zinc finger (PBZ) domain and is known to be involved in non-homologous end joining (NHEJ). Here, we identify a novel function of APLF involved in interstrand DNA crosslink (ICL) repair and fork protection. We demonstrate that PARP1 activity facilitates the APLF recruitment to stalled forks, enabling the FANCD2 recruitment to stalled forks. The depletion of APLF sensitizes cells to cisplatin, impairs ICL repair, reduces the FANCD2 recruitment to stalled forks, and results in nascent DNA degradation by MRE11 nucleases. Additionally, cisplatin-resistant cancer cells show high levels of APLF and homologous recombination-related gene expression. The depletion of APLF sensitizes cells to cisplatin and results in fork instability. Our results reveal the novel function of APLF to facilitate ICL repair and fork protection, thereby contributing to cisplatin-resistant phenotypes of cancer cells.

摘要

复制压力将停滞的叉转化为反转叉，这是防止叉降解和转化为有毒的 DNA 双链断裂 (DSB) 的重要保护机制。矛盾的是，该机制在癌细胞中也起到作用，有助于对各种 DNA 损伤剂产生化学抗性。PARP1 与停滞的叉子结合并被其激活，以促进叉子反转。 Aprataxin 和多核苷酸激酶/磷酸酶样因子 (APLF) 通过聚 (ADP-核糖) 锌指 (PBZ) 结构域与 PARP1 结合，已知其参与非同源末端连接 (NHEJ)。在这里，我们确定了 APLF 参与链间 DNA 交联 (ICL) 修复和叉子保护的新功能。我们证明 PARP1 活性促进 APLF 向停滞叉的募集，从而使 FANCD2 向停滞叉的募集成为可能。APLF 的耗竭使细胞对顺铂敏感，损害 ICL 修复，减少 FANCD2 向停滞叉的募集，并导致 MRE11 核酸酶对新生 DNA 的降解。此外，顺铂耐药的癌细胞表现出高水平的 APLF 和同源重组相关基因表达。APLF 的耗竭使细胞对顺铂敏感，并导致叉子不稳定。我们的结果揭示了 APLF 促进 ICL 修复和叉子保护的新功能，从而有助于癌细胞对顺铂耐药的表型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a640/11162786/9d4ea42a83a1/gkae211fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a640/11162786/134aed0e06b2/gkae211figgra1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a640/11162786/958123add411/gkae211fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a640/11162786/b41c8cb737ac/gkae211fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a640/11162786/170f37160d17/gkae211fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a640/11162786/828679faf705/gkae211fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a640/11162786/2dfd9c6ac319/gkae211fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a640/11162786/4ecd06b57262/gkae211fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a640/11162786/9bd9e1774d61/gkae211fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a640/11162786/46782d6f70b3/gkae211fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a640/11162786/9d4ea42a83a1/gkae211fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a640/11162786/134aed0e06b2/gkae211figgra1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a640/11162786/958123add411/gkae211fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a640/11162786/b41c8cb737ac/gkae211fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a640/11162786/170f37160d17/gkae211fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a640/11162786/828679faf705/gkae211fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a640/11162786/2dfd9c6ac319/gkae211fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a640/11162786/4ecd06b57262/gkae211fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a640/11162786/9bd9e1774d61/gkae211fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a640/11162786/46782d6f70b3/gkae211fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a640/11162786/9d4ea42a83a1/gkae211fig9.jpg

相似文献

1
APLF facilitates interstrand DNA crosslink repair and replication fork protection to confer cisplatin resistance.APLF 促进链间 DNA 交联修复和复制叉保护，从而赋予顺铂耐药性。
Nucleic Acids Res. 2024 Jun 10;52(10):5676-5697. doi: 10.1093/nar/gkae211.
2
Replication fork stability confers chemoresistance in BRCA-deficient cells.复制叉稳定性赋予BRCA缺陷细胞化学抗性。
Nature. 2016 Jul 21;535(7612):382-7. doi: 10.1038/nature18325.
3
Preventing over-resection by DNA2 helicase/nuclease suppresses repair defects in Fanconi anemia cells.通过DNA2解旋酶/核酸酶防止过度切除可抑制范科尼贫血细胞中的修复缺陷。
Cell Cycle. 2014;13(10):1540-50. doi: 10.4161/cc.28476. Epub 2014 Mar 12.
4
CtIP mediates replication fork recovery in a FANCD2-regulated manner.CtIP以FANCD2调节的方式介导复制叉恢复。
Hum Mol Genet. 2014 Jul 15;23(14):3695-705. doi: 10.1093/hmg/ddu078. Epub 2014 Feb 20.
5
FANCD2-controlled chromatin access of the Fanconi-associated nuclease FAN1 is crucial for the recovery of stalled replication forks.范可尼贫血相关核酸酶FAN1受FANCD2调控的染色质可及性对于停滞复制叉的恢复至关重要。
Mol Cell Biol. 2014 Nov;34(21):3939-54. doi: 10.1128/MCB.00457-14. Epub 2014 Aug 18.
6
Rewiring E2F1 with classical NHEJ via APLF suppression promotes bladder cancer invasiveness.通过抑制 APLF 利用经典 NHEJ 重编 E2F1 促进膀胱癌侵袭性。
J Exp Clin Cancer Res. 2019 Jul 8;38(1):292. doi: 10.1186/s13046-019-1286-9.
7
The PARP3- and ATM-dependent phosphorylation of APLF facilitates DNA double-strand break repair.APLF 的 PARP3 和 ATM 依赖性磷酸化促进 DNA 双链断裂修复。
Nucleic Acids Res. 2013 Apr;41(7):4080-92. doi: 10.1093/nar/gkt134. Epub 2013 Feb 28.
8
APLF (C2orf13) is a novel human protein involved in the cellular response to chromosomal DNA strand breaks.APLF（C2orf13）是一种新型人类蛋白质，参与细胞对染色体DNA链断裂的反应。
Mol Cell Biol. 2007 May;27(10):3793-803. doi: 10.1128/MCB.02269-06. Epub 2007 Mar 12.
9
FANCD2 and RAD51 recombinase directly inhibit DNA2 nuclease at stalled replication forks and FANCD2 acts as a novel RAD51 mediator in strand exchange to promote genome stability.FANCD2 和 RAD51 重组酶在停滞的复制叉处直接抑制 DNA2 核酸酶，并且 FANCD2 作为一种新型 RAD51 介体在链交换中起作用，以促进基因组稳定性。
Nucleic Acids Res. 2023 Sep 22;51(17):9144-9165. doi: 10.1093/nar/gkad624.
10
An Intrinsically Disordered APLF Links Ku, DNA-PKcs, and XRCC4-DNA Ligase IV in an Extended Flexible Non-homologous End Joining Complex.一种内在无序的APLF在扩展的灵活非同源末端连接复合物中连接Ku、DNA-PKcs和XRCC4-DNA连接酶IV。
J Biol Chem. 2016 Dec 30;291(53):26987-27006. doi: 10.1074/jbc.M116.751867. Epub 2016 Nov 14.

引用本文的文献

1
NUDT16 enhances the resistance of cancer cells to DNA-damaging agents by regulating replication fork stability via reversing HMGA1 ADP-ribosylation.NUDT16通过逆转HMGA1的ADP核糖基化来调节复制叉稳定性，从而增强癌细胞对DNA损伤剂的抗性。
J Biol Chem. 2025 Apr 25;301(6):108551. doi: 10.1016/j.jbc.2025.108551.
2
Tumor necrosis factor receptor-associated protein 1 promotes aerobic glycolysis and cisplatin resistance by regulating the Wnt/β-catenin signaling pathway in lung cancer.肿瘤坏死因子受体相关蛋白1通过调节肺癌中的Wnt/β-连环蛋白信号通路促进有氧糖酵解和顺铂耐药。
Histol Histopathol. 2024 Nov 26:18853. doi: 10.14670/HH-18-853.

本文引用的文献

1
APLF and long non-coding RNA NIHCOLE promote stable DNA synapsis in non-homologous end joining.APLF 和长非编码 RNA NIHCOLE 促进非同源末端连接中稳定的 DNA 连接。
Cell Rep. 2023 Jan 31;42(1):111917. doi: 10.1016/j.celrep.2022.111917. Epub 2022 Dec 31.
2
PARP1 recruits DNA translocases to restrain DNA replication and facilitate DNA repair.PARP1 将 DNA 转位酶募集到一起以抑制 DNA 复制并促进 DNA 修复。
PLoS Genet. 2022 Dec 13;18(12):e1010545. doi: 10.1371/journal.pgen.1010545. eCollection 2022 Dec.
3
DNA-PKcs promotes fork reversal and chemoresistance.
DNA-PKcs 促进叉突反转和化疗耐药性。
Mol Cell. 2022 Oct 20;82(20):3932-3942.e6. doi: 10.1016/j.molcel.2022.08.028. Epub 2022 Sep 20.
4
Chaperoning of the histone octamer by the acidic domain of DNA repair factor APLF.DNA 修复因子 APLF 的酸性结构域对组蛋白八聚体的介导作用。
Sci Adv. 2022 Jul 29;8(30):eabo0517. doi: 10.1126/sciadv.abo0517. Epub 2022 Jul 27.
5
Liquid-liquid phase separation drives cellular function and dysfunction in cancer.液液相分离驱动癌症中的细胞功能和功能障碍。
Nat Rev Cancer. 2022 Apr;22(4):239-252. doi: 10.1038/s41568-022-00444-7. Epub 2022 Feb 11.
6
The regulatory landscape of the human HPF1- and ARH3-dependent ADP-ribosylome.人类 HPF1 和 ARH3 依赖的 ADP-ribosylome 的调控景观。
Nat Commun. 2021 Oct 8;12(1):5893. doi: 10.1038/s41467-021-26172-4.
7
The HLTF-PARP1 interaction in the progression and stability of damaged replication forks caused by methyl methanesulfonate.甲磺酸甲酯引起的受损复制叉进展和稳定性中的HLTF-PARP1相互作用。
Oncogenesis. 2020 Dec 7;9(12):104. doi: 10.1038/s41389-020-00289-5.
8
An HPF1/PARP1-Based Chemical Biology Strategy for Exploring ADP-Ribosylation.基于 HPF1/PARP1 的化学生物学策略探索 ADP-核糖基化。
Cell. 2020 Nov 12;183(4):1086-1102.e23. doi: 10.1016/j.cell.2020.09.055.
9
Bridging of DNA breaks activates PARP2-HPF1 to modify chromatin.DNA 断裂的桥接激活 PARP2-HPF1 以修饰染色质。
Nature. 2020 Sep;585(7826):609-613. doi: 10.1038/s41586-020-2725-7. Epub 2020 Sep 16.
10
HPF1 completes the PARP active site for DNA damage-induced ADP-ribosylation.HPF1 完成了 PARP 活性部位，以促进 DNA 损伤诱导的 ADP-核糖基化。
Nature. 2020 Mar;579(7800):598-602. doi: 10.1038/s41586-020-2013-6. Epub 2020 Feb 6.