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在碱基切除修复过程中，UV-DDB 作为损伤传感器的作用。

Damage sensor role of UV-DDB during base excision repair.

机构信息

Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.

出版信息

Nat Struct Mol Biol. 2019 Aug;26(8):695-703. doi: 10.1038/s41594-019-0261-7. Epub 2019 Jul 22.

DOI:10.1038/s41594-019-0261-7
PMID:31332353
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6684372/
Abstract

UV-DDB, a key protein in human global nucleotide excision repair (NER), binds avidly to abasic sites and 8-oxo-guanine (8-oxoG), suggesting a noncanonical role in base excision repair (BER). We investigated whether UV-DDB can stimulate BER for these two common forms of DNA damage, 8-oxoG and abasic sites, which are repaired by 8-oxoguanine glycosylase (OGG1) and apurinic/apyrimidinic endonuclease (APE1), respectively. UV-DDB increased both OGG1 and APE1 strand cleavage and stimulated subsequent DNA polymerase β-gap filling activity by 30-fold. Single-molecule real-time imaging revealed that UV-DDB forms transient complexes with OGG1 or APE1, facilitating their dissociation from DNA. Furthermore, UV-DDB moves to sites of 8-oxoG repair in cells, and UV-DDB depletion sensitizes cells to oxidative DNA damage. We propose that UV-DDB is a general sensor of DNA damage in both NER and BER pathways, facilitating damage recognition in the context of chromatin.

摘要

UV-DDB 是人类全基因组核苷酸切除修复 (NER) 的关键蛋白，它能与碱基缺失和 8-氧鸟嘌呤 (8-oxoG) 紧密结合，这表明其在碱基切除修复 (BER) 中具有非典型作用。我们研究了 UV-DDB 是否能促进这两种常见 DNA 损伤（8-oxoG 和碱基缺失）的 BER，这两种损伤分别由 8-氧鸟嘌呤糖苷酶 (OGG1) 和脱嘌呤/脱嘧啶内切酶 (APE1) 修复。UV-DDB 可增加 OGG1 和 APE1 的链切割，并将随后的 DNA 聚合酶 β 缺口填充活性刺激 30 倍。单分子实时成像显示，UV-DDB 与 OGG1 或 APE1 形成短暂复合物，促进它们从 DNA 上解离。此外，UV-DDB 在细胞中移动到 8-oxoG 修复部位，UV-DDB 耗竭会使细胞对氧化 DNA 损伤敏感。我们提出，UV-DDB 是 NER 和 BER 途径中 DNA 损伤的通用传感器，促进了染色质背景下的损伤识别。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6bb/6684372/f1cd470ee717/nihms-1530419-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6bb/6684372/72c4fc7c2022/nihms-1530419-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6bb/6684372/7571931c843d/nihms-1530419-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6bb/6684372/48d455469359/nihms-1530419-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6bb/6684372/4cb2a958d7b5/nihms-1530419-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6bb/6684372/f1cd470ee717/nihms-1530419-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6bb/6684372/72c4fc7c2022/nihms-1530419-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6bb/6684372/7571931c843d/nihms-1530419-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6bb/6684372/48d455469359/nihms-1530419-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6bb/6684372/4cb2a958d7b5/nihms-1530419-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6bb/6684372/f1cd470ee717/nihms-1530419-f0005.jpg

相似文献

[1]
Damage sensor role of UV-DDB during base excision repair.

Nat Struct Mol Biol. 2019-7-22

[2]
The role of UV-DDB in processing 8-oxoguanine during base excision repair.

Biochem Soc Trans. 2022-10-31

[3]
UV-DDB as a General Sensor of DNA Damage in Chromatin: Multifaceted Approaches to Assess Its Direct Role in Base Excision Repair.

Int J Mol Sci. 2023-6-15

[4]
Modulation of the Apurinic/Apyrimidinic Endonuclease Activity of Human APE1 and of Its Natural Polymorphic Variants by Base Excision Repair Proteins.

Int J Mol Sci. 2020-9-28

[5]
Single molecule analysis indicates stimulation of MUTYH by UV-DDB through enzyme turnover.

Nucleic Acids Res. 2021-8-20

[6]
Global and transcription-coupled repair of 8-oxoG is initiated by nucleotide excision repair proteins.

Nat Commun. 2022-2-21

[7]
Dynamic Processing of a Common Oxidative DNA Lesion by the First Two Enzymes of the Base Excision Repair Pathway.

J Mol Biol. 2021-3-5

[8]
The role of the N-terminal domain of human apurinic/apyrimidinic endonuclease 1, APE1, in DNA glycosylase stimulation.

DNA Repair (Amst). 2018-2-11

[9]
Coordination of MYH DNA glycosylase and APE1 endonuclease activities via physical interactions.

DNA Repair (Amst). 2013-10-24

[10]
DDB1-DDB2 (xeroderma pigmentosum group E) protein complex recognizes a cyclobutane pyrimidine dimer, mismatches, apurinic/apyrimidinic sites, and compound lesions in DNA.

J Biol Chem. 2005-12-2

引用本文的文献

[1]
XPC-RAD23B enhances UV-DDB binding to DNA to facilitate lesion search in nucleotide excision repair.

Nucleic Acids Res. 2025-6-6

[2]
A novel high-throughput single-molecule technique DNA curtain: Applications for DNA metabolism.

Mol Cells. 2025-7

[3]
Metabolic Rewiring in the Face of Genomic Assault: Integrating DNA Damage Response and Cellular Metabolism.

Biomolecules. 2025-1-23

[4]
Single-molecule studies of repair proteins in base excision repair.

BMB Rep. 2025-1

[5]
Probing the mechanism of nick searching by LIG1 at the single-molecule level.

Nucleic Acids Res. 2024-11-11

[6]
Mitochondrial defects in sporadic inclusion body myositis-causes and consequences.

Front Cell Dev Biol. 2024-5-14

[7]
Development of Peptide Displacement Assays to Screen for Antagonists of DDB1 Interactions.

Biochemistry. 2024-5-21

[8]
Single-molecule analysis of purified proteins and nuclear extracts: Insights from 8-oxoguanine glycosylase 1.

DNA Repair (Amst). 2024-2

[9]
Back-Up Base Excision DNA Repair in Human Cells Deficient in the Major AP Endonuclease, APE1.

Int J Mol Sci. 2023-12-20

[10]
UV-DDB as a General Sensor of DNA Damage in Chromatin: Multifaceted Approaches to Assess Its Direct Role in Base Excision Repair.

Int J Mol Sci. 2023-6-15

本文引用的文献

[1]
Targeted and Persistent 8-Oxoguanine Base Damage at Telomeres Promotes Telomere Loss and Crisis.

Mol Cell. 2019-5-14

[2]
Fe-S Clusters and MutY Base Excision Repair Glycosylases: Purification, Kinetics, and DNA Affinity Measurements.

Methods Enzymol. 2018

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Human Oxoguanine Glycosylase 1 Removes Solution Accessible 8-Oxo-7,8-dihydroguanine Lesions from Globally Substituted Nucleosomes Except in the Dyad Region.

Biochemistry. 2018-3-6

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PARP1 changes from three-dimensional DNA damage searching to one-dimensional diffusion after auto-PARylation or in the presence of APE1.

Nucleic Acids Res. 2017-12-15

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Human OGG1 activity in nucleosomes is facilitated by transient unwrapping of DNA and is influenced by the local histone environment.

DNA Repair (Amst). 2017-11

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DNA Repair (Amst). 2017-9

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Single-Molecule Methods for Nucleotide Excision Repair: Building a System to Watch Repair in Real Time.

Methods Enzymol. 2017

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J Bacteriol. 2016-5-27

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A genetically targetable near-infrared photosensitizer.

Nat Methods. 2016-3

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Capturing snapshots of APE1 processing DNA damage.

Nat Struct Mol Biol. 2015-11

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