scholarly journals Function and Interactions of ERCC1-XPF in DNA Damage Response

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3205 ◽  
Author(s):  
Maryam Faridounnia ◽  
Gert Folkers ◽  
Rolf Boelens
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Excision Repair ◽  
Strand Break ◽  
Response Network ◽  
Nucleotide Excision ◽  
Damage Response ◽  
Human Disorders ◽  
Heterodimeric Complex ◽  
Repair Pathways

Numerous proteins are involved in the multiple pathways of the DNA damage response network and play a key role to protect the genome from the wide variety of damages that can occur to DNA. An example of this is the structure-specific endonuclease ERCC1-XPF. This heterodimeric complex is in particular involved in nucleotide excision repair (NER), but also in double strand break repair and interstrand cross-link repair pathways. Here we review the function of ERCC1-XPF in various DNA repair pathways and discuss human disorders associated with ERCC1-XPF deficiency. We also overview our molecular and structural understanding of XPF-ERCC1.

scholarly journals Nucleotide excision repair–induced H2A ubiquitination is dependent on MDC1 and RNF8 and reveals a universal DNA damage response

2009 ◽  
Vol 186 (6) ◽  
pp. 835-847 ◽  
Author(s):  
Jurgen A. Marteijn ◽  
Simon Bekker-Jensen ◽  
Niels Mailand ◽  
Hannes Lans ◽  
Petra Schwertman ◽  
...  
Keyword(s):  
Dna Damage ◽  
Nucleotide Excision Repair ◽  
Dna Damage Response ◽  
Excision Repair ◽  
Strand Break ◽  
Epigenetic Mark ◽  
Histone H2a ◽  
Nucleotide Excision ◽  
Damage Response ◽  
Damaged Dna

Chromatin modifications are an important component of the of DNA damage response (DDR) network that safeguard genomic integrity. Recently, we demonstrated nucleotide excision repair (NER)–dependent histone H2A ubiquitination at sites of ultraviolet (UV)-induced DNA damage. In this study, we show a sustained H2A ubiquitination at damaged DNA, which requires dynamic ubiquitination by Ubc13 and RNF8. Depletion of these enzymes causes UV hypersensitivity without affecting NER, which is indicative of a function for Ubc13 and RNF8 in the downstream UV–DDR. RNF8 is targeted to damaged DNA through an interaction with the double-strand break (DSB)–DDR scaffold protein MDC1, establishing a novel function for MDC1. RNF8 is recruited to sites of UV damage in a cell cycle–independent fashion that requires NER-generated, single-stranded repair intermediates and ataxia telangiectasia–mutated and Rad3-related protein. Our results reveal a conserved pathway of DNA damage–induced H2A ubiquitination for both DSBs and UV lesions, including the recruitment of 53BP1 and Brca1. Although both lesions are processed by independent repair pathways and trigger signaling responses by distinct kinases, they eventually generate the same epigenetic mark, possibly functioning in DNA damage signal amplification.

scholarly journals Nucleotide Excision Repair Protein Rad23 Regulates Cell Virulence Independent of Rad4 in Candida albicans

mSphere ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Jia Feng ◽  
Shuangyan Yao ◽  
Yansong Dong ◽  
Jing Hu ◽  
Malcolm Whiteway ◽  
...  
Keyword(s):  
Dna Damage ◽  
Candida Albicans ◽  
Nucleotide Excision Repair ◽  
Dna Damage Response ◽  
Excision Repair ◽  
Content Type ◽  
Virulence Regulation ◽  
Nucleotide Excision ◽  
Damage Response

ABSTRACT In the pathogenic yeast Candida albicans, the DNA damage response contributes to pathogenicity by regulating cell morphology transitions and maintaining survival in response to DNA damage induced by reactive oxygen species (ROS) in host cells. However, the function of nucleotide excision repair (NER) in C. albicans has not been extensively investigated. To better understand the DNA damage response and its role in virulence, we studied the function of the Rad23 nucleotide excision repair protein in detail. The RAD23 deletion strain and overexpression strain both exhibit UV sensitivity, confirming the critical role of RAD23 in the nucleotide excision repair pathway. Genetic interaction assays revealed that the role of RAD23 in the UV response relies on RAD4 but is independent of RAD53, MMS22, and RAD18. RAD4 and RAD23 have similar roles in regulating cell morphogenesis and biofilm formation; however, only RAD23, but not RAD4, plays a negative role in virulence regulation in a mouse model. We found that the RAD23 deletion strain showed decreased survival in a Candida-macrophage interaction assay. Transcriptome sequencing (RNA-seq) and quantitative real-time PCR (qRT-PCR) data further revealed that RAD23, but not RAD4, regulates the transcription of a virulence factor, SUN41, suggesting a unique role of RAD23 in virulence regulation. Taking these observations together, our work reveals that the RAD23-related nucleotide excision pathway plays a critical role in the UV response but may not play a direct role in virulence. The virulence-related role of RAD23 may rely on the regulation of several virulence factors, which may give us further understanding about the linkage between DNA damage repair and virulence regulation in C. albicans. IMPORTANCE Candida albicans remains a significant threat to the lives of immunocompromised people. An understanding of the virulence and infection ability of C. albicans cells in the mammalian host may help with clinical treatment and drug discovery. The DNA damage response pathway is closely related to morphology regulation and virulence, as well as the ability to survive in host cells. In this study, we checked the role of the nucleotide excision repair (NER) pathway, the key repair system that functions to remove a large variety of DNA lesions such as those caused by UV light, but whose function has not been well studied in C. albicans. We found that Rad23, but not Rad4, plays a role in virulence that appears independent of the function of the NER pathway. Our research revealed that the NER pathway represented by Rad4/Rad23 may not play a direct role in virulence but that Rad23 may play a unique role in regulating the transcription of virulence genes that may contribute to the virulence of C. albicans.

scholarly journals DDB2 (Damaged-DNA binding protein 2) in nucleotide excision repair and DNA damage response

Cell Cycle ◽  
2009 ◽  
Vol 8 (24) ◽  
pp. 4067-4071 ◽  
Author(s):  
Tanya Stoyanova ◽  
Nilotpal Roy ◽  
Dragana Kopanja ◽  
Pradip Raychaudhuri ◽  
Srilata Bagchi
Keyword(s):  
Dna Damage ◽  
Dna Binding ◽  
Nucleotide Excision Repair ◽  
Dna Damage Response ◽  
Excision Repair ◽  
Binding Protein ◽  
Dna Binding Protein ◽  
Nucleotide Excision ◽  
Damage Response ◽  
Damaged Dna

scholarly journals Rescue of cells from apoptosis increases DNA repair in UVB exposed cells: implications for the DNA damage response

2015 ◽  
Vol 4 (3) ◽  
pp. 725-738 ◽  
Author(s):  
Mahsa Karbaschi ◽  
Salvador Macip ◽  
Vilas Mistry ◽  
Hussein H. K. Abbas ◽  
George J. Delinassios ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Nucleotide Excision Repair ◽  
Dna Damage Response ◽  
Excision Repair ◽  
Cyclobutane Pyrimidine Dimers ◽  
Pyrimidine Dimers ◽  
Nucleotide Excision ◽  
Damage Response ◽  
Lengthy Process

Classically, the nucleotide excision repair (NER) of cyclobutane pyrimidine dimers (CPD) is a lengthy process (t1/2 > 48 h).

scholarly journals RNF111/Arkadia is a SUMO-targeted ubiquitin ligase that facilitates the DNA damage response

2013 ◽  
Vol 201 (6) ◽  
pp. 797-807 ◽  
Author(s):  
Sara L. Poulsen ◽  
Rebecca K. Hansen ◽  
Sebastian A. Wagner ◽  
Loes van Cuijk ◽  
Gijsbert J. van Belle ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Excision Repair ◽  
Protein A ◽  
C Protein ◽  
Target Proteins ◽  
Damage Recognition ◽  
Nucleotide Excision ◽  
Damage Response ◽  
Dna Damage Recognition

Protein modifications by ubiquitin and small ubiquitin-like modifier (SUMO) play key roles in cellular signaling pathways. SUMO-targeted ubiquitin ligases (STUbLs) directly couple these modifications by selectively recognizing SUMOylated target proteins through SUMO-interacting motifs (SIMs), promoting their K48-linked ubiquitylation and degradation. Only a single mammalian STUbL, RNF4, has been identified. We show that human RNF111/Arkadia is a new STUbL, which used three adjacent SIMs for specific recognition of poly-SUMO2/3 chains, and used Ubc13–Mms2 as a cognate E2 enzyme to promote nonproteolytic, K63-linked ubiquitylation of SUMOylated target proteins. We demonstrate that RNF111 promoted ubiquitylation of SUMOylated XPC (xeroderma pigmentosum C) protein, a central DNA damage recognition factor in nucleotide excision repair (NER) extensively regulated by ultraviolet (UV)-induced SUMOylation and ubiquitylation. Moreover, we show that RNF111 facilitated NER by regulating the recruitment of XPC to UV-damaged DNA. Our findings establish RNF111 as a new STUbL that directly links nonproteolytic ubiquitylation and SUMOylation in the DNA damage response.

scholarly journals Different Effects of CSA and CSB Deficiency on Sensitivity to Oxidative DNA Damage

2004 ◽  
Vol 24 (18) ◽  
pp. 7941-7948 ◽  
Author(s):  
Harm de Waard ◽  
Jan de Wit ◽  
Jaan-Olle Andressoo ◽  
Conny T. M. van Oostrom ◽  
Bente Riis ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Oxidative Dna Damage ◽  
Gamma Ray ◽  
Excision Repair ◽  
Embryonic Stem ◽  
Cockayne Syndrome ◽  
Nucleotide Excision ◽  
Damage Response ◽  
Transcription Coupled Repair

ABSTRACT Mutations in the CSA and CSB genes cause Cockayne syndrome, a rare inherited disorder characterized by UV sensitivity, severe neurological abnormalities, and progeriod symptoms. Both gene products function in the transcription-coupled repair (TCR) subpathway of nucleotide excision repair (NER), providing the cell with a mechanism to remove transcription-blocking lesions from the transcribed strands of actively transcribed genes. Besides a function in TCR of NER lesions, a role of CSB in (transcription-coupled) repair of oxidative DNA damage has been suggested. In this study we used mouse models to compare the effect of a CSA or a CSB defect on oxidative DNA damage sensitivity at the levels of the cell and the intact organism. In contrast to CSB −/− mouse embryonic fibroblasts (MEFs), CSA −/− MEFs are not hypersensitive to gamma-ray or paraquat treatment. Similar results were obtained for keratinocytes. In contrast, both CSB −/− and CSA −/− embryonic stem cells show slight gamma-ray sensitivity. Finally, CSB −/− but not CSA −/− mice fed with food containing di(2-ethylhexyl)phthalate (causing elevated levels of oxidative DNA damage in the liver) show weight reduction. These findings not only uncover a clear difference in oxidative DNA damage sensitivity between CSA- and CSB-deficient cell lines and mice but also show that sensitivity to oxidative DNA damage is not a uniform characteristic of Cockayne syndrome. This difference in the DNA damage response between CSA- and CSB-deficient cells is unexpected, since until now no consistent differences between CSA and CSB patients have been reported. We suggest that the CSA and CSB proteins in part perform separate roles in different DNA damage response pathways.

scholarly journals Sites of Acetylation on Newly Synthesized Histone H4 Are Required for Chromatin Assembly and DNA Damage Response Signaling

2013 ◽  
Vol 33 (16) ◽  
pp. 3286-3298 ◽  
Author(s):  
Zhongqi Ge ◽  
Devi Nair ◽  
Xiaoyan Guan ◽  
Neha Rastogi ◽  
Michael A. Freitas ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Histone H3 ◽  
Model Organism ◽  
Strand Break ◽  
Chromatin Assembly ◽  
Histone H4 ◽  
Histone H4 Acetylation ◽  
Damage Response ◽  
A Site

The best-characterized acetylation of newly synthesized histone H4 is the diacetylation of the NH2-terminal tail on lysines 5 and 12. Despite its evolutionary conservation, this pattern of modification has not been shown to be essential for either viability or chromatin assembly in any model organism. We demonstrate that mutations in histone H4 lysines 5 and 12 in yeast confer hypersensitivity to replication stress and DNA-damaging agents when combined with mutations in histone H4 lysine 91, which has also been found to be a site of acetylation on soluble histone H4. In addition, these mutations confer a dramatic decrease in cell viability when combined with mutations in histone H3 lysine 56. We also show that mutation of the sites of acetylation on newly synthesized histone H4 results in defects in the reassembly of chromatin structure that accompanies the repair of HO-mediated double-strand breaks. This defect is not due to a decrease in the level of histone H3 lysine 56 acetylation. Intriguingly, mutations that alter the sites of newly synthesized histone H4 acetylation display a marked decrease in levels of phosphorylated H2A (γ-H2AX) in chromatin surrounding the double-strand break. These results indicate that the sites of acetylation on newly synthesized histones H3 and H4 can function in nonoverlapping ways that are required for chromatin assembly, viability, and DNA damage response signaling.

WDNfinder: A method for minimum driver node set detection and analysis in directed and weighted biological network

2017 ◽  
Vol 15 (05) ◽  
pp. 1750021 ◽  
Author(s):  
Yanshuo Chu ◽  
Zhenxing Wang ◽  
Rongjie Wang ◽  
Ningyi Zhang ◽  
Jie Li ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Biological Networks ◽  
Domain Knowledge ◽  
Human Cancer ◽  
Accurate Analysis ◽  
Response Network ◽  
Public Data ◽  
Damage Response ◽  
Structural Controllability

Structural controllability is the generalization of traditional controllability for dynamical systems. During the last decade, interesting biological discoveries have been inferred by applied structural controllability analysis to biological networks. However, false positive/negative information (i.e. nodes and edges) widely exists in biological networks that documented in public data sources, which can hinder accurate analysis of structural controllability. In this study, we propose WDNfinder, a comprehensive analysis package that provides structural controllability with consideration of node connection strength in biological networks. When applied to the human cancer signaling network and p53-mediate DNA damage response network, WDNfinder shows high accuracy on essential nodes prediction in these networks. Compared to existing methods, WDNfinder can significantly narrow down the set of minimum driver node set (MDS) under the restriction of domain knowledge. When using p53-mediate DNA damage response network as illustration, we find more meaningful MDSs by WDNfinder. The source code is implemented in python and publicly available together with relevant data on GitHub: https://github.com/dustincys/WDNfinder .

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