scholarly journals Nucleotide excision repair leaves a mark on chromatin: DNA damage detection in nucleosomes

2021 ◽  
Author(s):  
Katja Apelt ◽  
Hannes Lans ◽  
Orlando D. Schärer ◽  
Martijn S. Luijsterburg
Keyword(s):  
Dna Damage ◽  
Damage Detection ◽  
Nucleotide Excision Repair ◽  
Genomic Dna ◽  
Excision Repair ◽  
Dna Lesions ◽  
Post Translational Modifications ◽  
Nucleosomal Dna ◽  
Nucleotide Excision ◽  
Dna Repair Proteins

AbstractGlobal genome nucleotide excision repair (GG-NER) eliminates a broad spectrum of DNA lesions from genomic DNA. Genomic DNA is tightly wrapped around histones creating a barrier for DNA repair proteins to access DNA lesions buried in nucleosomal DNA. The DNA-damage sensors XPC and DDB2 recognize DNA lesions in nucleosomal DNA and initiate repair. The emerging view is that a tight interplay between XPC and DDB2 is regulated by post-translational modifications on the damage sensors themselves as well as on chromatin containing DNA lesions. The choreography between XPC and DDB2, their interconnection with post-translational modifications such as ubiquitylation, SUMOylation, methylation, poly(ADP-ribos)ylation, acetylation, and the functional links with chromatin remodelling activities regulate not only the initial recognition of DNA lesions in nucleosomes, but also the downstream recruitment and necessary displacement of GG-NER factors as repair progresses. In this review, we highlight how nucleotide excision repair leaves a mark on chromatin to enable DNA damage detection in nucleosomes.

scholarly journals Versatile DNA damage detection by the global genome nucleotide excision repair protein XPC

2008 ◽  
Vol 121 (17) ◽  
pp. 2850-2859 ◽  
Author(s):  
D. Hoogstraten ◽  
S. Bergink ◽  
J. M. Y. Ng ◽  
V. H. M. Verbiest ◽  
M. S. Luijsterburg ◽  
...  
Keyword(s):  
Dna Damage ◽  
Damage Detection ◽  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Repair Protein ◽  
Nucleotide Excision ◽  
Nucleotide Excision Repair Protein

scholarly journals Versatile DNA damage detection by the global genome nucleotide excision repair protein XPC

2008 ◽  
Vol 121 (17) ◽  
pp. 2972-2972
Author(s):  
D. Hoogstraten ◽  
S. Bergink ◽  
V. H. M. Verbiest ◽  
M. S. Luijsterburg ◽  
B. Geverts ◽  
...  
Keyword(s):  
Dna Damage ◽  
Damage Detection ◽  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Repair Protein ◽  
Nucleotide Excision ◽  
Nucleotide Excision Repair Protein

scholarly journals Versatile DNA damage detection by the global genome nucleotide excision repair protein XPC

2008 ◽  
Vol 121 (23) ◽  
pp. 3991-3991 ◽  
Author(s):  
D. Hoogstraten ◽  
S. Bergink ◽  
J. M. Y. Ng ◽  
V. H. M. Verbiest ◽  
M. S. Luijsterburg ◽  
...  
Keyword(s):  
Dna Damage ◽  
Damage Detection ◽  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Repair Protein ◽  
Nucleotide Excision ◽  
Nucleotide Excision Repair Protein

scholarly journals Cryo-EM structure of TFIIH/Rad4–Rad23–Rad33 in damaged DNA opening in nucleotide excision repair

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Trevor van Eeuwen ◽  
Yoonjung Shim ◽  
Hee Jong Kim ◽  
Tingting Zhao ◽  
Shrabani Basu ◽  
...  
Keyword(s):  
Nucleotide Excision Repair ◽  
Genomic Dna ◽  
Excision Repair ◽  
Dna Lesions ◽  
Dna Adduct ◽  
Dna Unwinding ◽  
General Transcription Factor ◽  
Nucleotide Excision ◽  
Torque Generation ◽  
Transcription Factor Complex

AbstractThe versatile nucleotide excision repair (NER) pathway initiates as the XPC–RAD23B–CETN2 complex first recognizes DNA lesions from the genomic DNA and recruits the general transcription factor complex, TFIIH, for subsequent lesion verification. Here, we present a cryo-EM structure of an NER initiation complex containing Rad4–Rad23-Rad33 (yeast homologue of XPC–RAD23B–CETN2) and 7-subunit coreTFIIH assembled on a carcinogen-DNA adduct lesion at 3.9–9.2 Å resolution. A ~30-bp DNA duplex could be mapped as it straddles between Rad4 and the Ssl2 (XPB) subunit of TFIIH on the 3' and 5' side of the lesion, respectively. The simultaneous binding with Rad4 and TFIIH was permitted by an unwinding of DNA at the lesion. Translocation coupled with torque generation by Ssl2 and Rad4 would extend the DNA unwinding at the lesion and deliver the damaged strand to Rad3 (XPD) in an open form suitable for subsequent lesion scanning and verification.

scholarly journals The TFIIH subunits p44/p62 act as a damage sensor during nucleotide excision repair

2019 ◽  
Author(s):  
JT Barnett ◽  
J Kuper ◽  
W Koelmel ◽  
C Kisker ◽  
NM Kad
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Binding ◽  
Nucleotide Excision Repair ◽  
Single Molecule ◽  
Excision Repair ◽  
Uv Light ◽  
Dna Lesions ◽  
The Core ◽  
Nucleotide Excision

AbstractNucleotide excision repair (NER) protects the genome following exposure to diverse types of DNA damage, including UV light and chemotherapeutics. Mutations in mammalian NER genes lead to diseases such as xeroderma pigmentosum, trichothiodystrophy, and Cockayne syndrome. In eukaryotes, the major transcription factor TFIIH is the central hub of NER. The core components of TFIIH include the helicases XPB, XPD, and five ‘structural’ subunits. Two of these structural TFIIH proteins, p44 and p62 remain relatively unstudied; p44 is known to regulate the helicase activity of XPD during NER whereas p62’s role is thought to be structural. However, a recent cryo-EM structure shows that p44, p62, and XPD make extensive contacts within TFIIH, with part of p62 occupying XPD’s DNA binding site. This observation implies a more extensive role in DNA repair beyond the structural integrity of TFIIH. Here, we show that p44 stimulates XPD’s ATPase but upon encountering DNA damage, further stimulation is only observed when p62 is part of the ternary complex; suggesting a role for the p44/p62 heterodimer in TFIIH’s mechanism of damage detection. Using single molecule imaging, we demonstrate that p44/p62 independently interacts with DNA; it is seen to diffuse, however, in the presence of UV-induced DNA lesions the complex stalls. Combined with the analysis of a recent cryo-EM structure we suggest that p44/p62 acts as a novel DNA-binding entity within TFIIH that is capable of recognizing DNA damage. This revises our understanding of TFIIH and prompts more extensive investigation into the core subunits for an active role during both DNA repair and transcription.

scholarly journals Nucleotide excision repair genes shaping embryonic development

Open Biology ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 190166 ◽  
Author(s):  
Sofia J. Araújo ◽  
Isao Kuraoka
Keyword(s):  
Dna Damage ◽  
Embryonic Development ◽  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Current Knowledge ◽  
Dna Lesions ◽  
Accelerated Ageing ◽  
Developmental Abnormalities ◽  
Nucleotide Excision ◽  
Human Disorders

Nucleotide excision repair (NER) is a highly conserved mechanism to remove helix-distorting DNA lesions. A major substrate for NER is DNA damage caused by environmental genotoxins, most notably ultraviolet radiation. Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy are three human disorders caused by inherited defects in NER. The symptoms and severity of these diseases vary dramatically, ranging from profound developmental delay to cancer predisposition and accelerated ageing. All three syndromes include developmental abnormalities, indicating an important role for optimal transcription and for NER in protecting against spontaneous DNA damage during embryonic development. Here, we review the current knowledge on genes that function in NER that also affect embryonic development, in particular the development of a fully functional nervous system.

scholarly journals DICER- and MMSET-catalyzed H4K20me2 recruits the nucleotide excision repair factor XPA to DNA damage sites

2017 ◽  
Vol 217 (2) ◽  
pp. 527-540 ◽  
Author(s):  
Shalaka Chitale ◽  
Holger Richly
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Uv Light ◽  
Dna Lesions ◽  
Histone H4 ◽  
Damage Site ◽  
Nucleotide Excision ◽  
Lesion Recognition

Ultraviolet (UV) irradiation triggers the recruitment of DNA repair factors to the lesion sites and the deposition of histone marks as part of the DNA damage response. The major DNA repair pathway removing DNA lesions caused by exposure to UV light is nucleotide excision repair (NER). We have previously demonstrated that the endoribonuclease DICER facilitates chromatin decondensation during lesion recognition in the global-genomic branch of NER. Here, we report that DICER mediates the recruitment of the methyltransferase MMSET to the DNA damage site. We show that MMSET is required for efficient NER and that it catalyzes the dimethylation of histone H4 at lysine 20 (H4K20me2). H4K20me2 at DNA damage sites facilitates the recruitment of the NER factor XPA. Our work thus provides evidence for an H4K20me2-dependent mechanism of XPA recruitment during lesion recognition in the global-genomic branch of NER.

scholarly journals Ubiquitin and TFIIH-stimulated DDB2 dissociation drives DNA damage handover in nucleotide excision repair

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Cristina Ribeiro-Silva ◽  
Mariangela Sabatella ◽  
Angela Helfricht ◽  
Jurgen A. Marteijn ◽  
Arjan F. Theil ◽  
...  
Keyword(s):  
Dna Damage ◽  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Repair Process ◽  
Dna Lesions ◽  
Damage Recognition ◽  
Nucleotide Excision ◽  
Repair Factor ◽  
Dna Damage Recognition ◽  
Spatiotemporal Control

Abstract DNA damage sensors DDB2 and XPC initiate global genome nucleotide excision repair (NER) to protect DNA from mutagenesis caused by helix-distorting lesions. XPC recognizes helical distortions by binding to unpaired ssDNA opposite DNA lesions. DDB2 binds to UV-induced lesions directly and facilitates efficient recognition by XPC. We show that not only lesion-binding but also timely DDB2 dissociation is required for DNA damage handover to XPC and swift progression of the multistep repair reaction. DNA-binding-induced DDB2 ubiquitylation and ensuing degradation regulate its homeostasis to prevent excessive lesion (re)binding. Additionally, damage handover from DDB2 to XPC coincides with the arrival of the TFIIH complex, which further promotes DDB2 dissociation and formation of a stable XPC-TFIIH damage verification complex. Our results reveal a reciprocal coordination between DNA damage recognition and verification within NER and illustrate that timely repair factor dissociation is vital for correct spatiotemporal control of a multistep repair process.

scholarly journals Recognition of DNA damage by XPC coincides with disruption of the XPC–RAD23 complex

2012 ◽  
Vol 196 (6) ◽  
pp. 681-688 ◽  
Author(s):  
Steven Bergink ◽  
Wendy Toussaint ◽  
Martijn S. Luijsterburg ◽  
Christoffel Dinant ◽  
Sergey Alekseev ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Nucleotide Excision Repair ◽  
Deoxyribonucleic Acid ◽  
Excision Repair ◽  
Proteasomal Degradation ◽  
Repair Process ◽  
Dna Lesions ◽  
Direct Role ◽  
Nucleotide Excision

The recognition of helix-distorting deoxyribonucleic acid (DNA) lesions by the global genome nucleotide excision repair subpathway is performed by the XPC–RAD23–CEN2 complex. Although it has been established that Rad23 homologs are essential to protect XPC from proteasomal degradation, it is unclear whether RAD23 proteins have a direct role in the recognition of DNA damage. In this paper, we show that the association of XPC with ultraviolet-induced lesions was impaired in the absence of RAD23 proteins. Furthermore, we show that RAD23 proteins rapidly dissociated from XPC upon binding to damaged DNA. Our data suggest that RAD23 proteins facilitate lesion recognition by XPC but do not participate in the downstream DNA repair process.

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