scholarly journals Double-Strand Break Formation during Nucleotide Excision Repair of a DNA Interstrand Cross-Link

Biochemistry ◽  
2009 ◽  
Vol 48 (32) ◽  
pp. 7565-7567 ◽  
Author(s):  
Jonathan T. Sczepanski ◽  
Aaron C. Jacobs ◽  
Bennett Van Houten ◽  
Marc M. Greenberg
Keyword(s):  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Strand Break ◽  
Double Strand Break ◽  
Cross Link ◽  
Nucleotide Excision ◽  
Break Formation

Ubiquitin and SUMO signalling in DNA repair

2010 ◽  
Vol 38 (1) ◽  
pp. 116-131 ◽  
Author(s):  
Timothy M. Thomson ◽  
Marta Guerra-Rebollo
Keyword(s):  
Dna Repair ◽  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Translesion Synthesis ◽  
Strand Break ◽  
Cross Link ◽  
Post Translational Modifications ◽  
Nucleotide Excision ◽  
Specific Proteins ◽  
Modified Proteins

The repair of lesions and gaps in DNA follows different pathways, each mediated by specific proteins and complexes. Post-translational modifications in many of these proteins govern their activities and interactions, ultimately determining whether a particular pathway is followed. Prominent among these modifications are the addition of phosphate or ubiquitin (and ubiquitin-like) moieties that confer new binding surfaces and conformational states on the modified proteins. The present review summarizes some of consequences of ubiquitin and ubiquitin-like modifications and interactions that regulate nucleotide excision repair, translesion synthesis, double-strand break repair and interstrand cross-link repair, with the discussion of relevant examples in each pathway.

scholarly journals A Synthetic Interaction between CDC20 and RAD4 in Saccharomyces cerevisiae upon UV Irradiation

2014 ◽  
Vol 2014 ◽  
pp. 1-8
Author(s):  
Bernadette Connors ◽  
Lauren Rochelle ◽  
Asela Roberts ◽  
Graham Howard
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Nucleotide Excision Repair ◽  
Uv Irradiation ◽  
Double Mutant ◽  
Excision Repair ◽  
Strand Break ◽  
Anaphase Promoting Complex ◽  
End Joining ◽  
Ubiquitin Ligase Complex ◽  
Nucleotide Excision

Regulation of DNA repair can be achieved through ubiquitin-mediated degradation of transiently induced proteins. In Saccharomyces cerevisiae, Rad4 is involved in damage recognition during nucleotide excision repair (NER) and, in conjunction with Rad23, recruits other proteins to the site of damage. We identified a synthetic interaction upon UV exposure between Rad4 and Cdc20, a protein that modulates the activity of the anaphase promoting complex (APC/C), a multisubunit E3 ubiquitin ligase complex. The moderately UV sensitive Δrad4 strain became highly sensitive when cdc20-1 was present, and was rescued by overexpression of CDC20. The double mutant is also deficient in elicting RNR3-lacZ transcription upon exposure to UV irradiation or 4-NQO compared with the Δrad4 single mutant. We demonstrate that the Δrad4/cdc20-1 double mutant is defective in double strand break repair by way of a plasmid end-joining assay, indicating that Rad4 acts to ensure that damaged DNA is repaired via a Cdc20-mediated mechanism. This study is the first to present evidence that Cdc20 may play a role in the degradation of proteins involved in nucleotide excision repair.

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 Elevated glucose increases genomic instability by inhibiting nucleotide excision repair

2021 ◽  
Vol 4 (10) ◽  
pp. e202101159
Author(s):  
Alexandra K Ciminera ◽  
Sarah C Shuck ◽  
John Termini
Keyword(s):  
Dna Repair ◽  
Genomic Instability ◽  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Hypoxia Inducible Factor ◽  
Strand Break ◽  
Strand Breaks ◽  
Nucleotide Excision ◽  
Elevated Glucose ◽  
Dna Strand

We investigated potential mechanisms by which elevated glucose may promote genomic instability. Gene expression studies, protein measurements, mass spectroscopic analyses, and functional assays revealed that elevated glucose inhibited the nucleotide excision repair (NER) pathway, promoted DNA strand breaks, and increased levels of the DNA glycation adduct N2-(1-carboxyethyl)-2ʹ-deoxyguanosine (CEdG). Glycation stress in NER-competent cells yielded single-strand breaks accompanied by ATR activation, γH2AX induction, and enhanced non-homologous end-joining and homology-directed repair. In NER-deficient cells, glycation stress activated ATM/ATR/H2AX, consistent with double-strand break formation. Elevated glucose inhibited DNA repair by attenuating hypoxia-inducible factor-1α–mediated transcription of NER genes via enhanced 2-ketoglutarate–dependent prolyl hydroxylase (PHD) activity. PHD inhibition enhanced transcription of NER genes and facilitated CEdG repair. These results are consistent with a role for hyperglycemia in promoting genomic instability as a potential mechanism for increasing cancer risk in metabolic disease. Because of the pleiotropic functions of many NER genes beyond DNA repair, these results may have broader implications for cellular pathophysiology.

scholarly journals Involvement of Nucleotide Excision Repair in a Recombination-Independent and Error-Prone Pathway of DNA Interstrand Cross-Link Repair

2001 ◽  
Vol 21 (3) ◽  
pp. 713-720 ◽  
Author(s):  
Xin Wang ◽  
Carolyn A. Peterson ◽  
Huyong Zheng ◽  
Rodney S. Nairn ◽  
Randy J. Legerski ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Nucleotide Excision Repair ◽  
Mammalian Cells ◽  
Cultured Cells ◽  
Excision Repair ◽  
Repair Pathway ◽  
Cross Link ◽  
Nucleotide Excision ◽  
Interstrand Cross Links ◽  
Cross Links

ABSTRACT DNA interstrand cross-links (ICLs) block the strand separation necessary for essential DNA functions such as transcription and replication and, hence, represent an important class of DNA lesion. Since both strands of the double helix are affected in cross-linked DNA, it is likely that conservative recombination using undamaged homologous regions as a donor may be required to repair ICLs in an error-free manner. However, in Escherichia coli and yeast, recombination-independent mechanisms of ICL repair have been identified in addition to recombinational repair pathways. To study the repair mechanisms of interstrand cross-links in mammalian cells, we developed an in vivo reactivation assay to examine the removal of interstrand cross-links in cultured cells. A site-specific psoralen cross-link was placed between the promoter and the coding region to inactivate the expression of green fluorescent protein or luciferase genes from reporter plasmids. By monitoring the reactivation of the reporter gene, we showed that a single defined psoralen cross-link was removed in repair-proficient cells in the absence of undamaged homologous sequences, suggesting the existence of an ICL repair pathway that is independent of homologous recombination. Mutant cell lines deficient in the nucleotide excision repair pathway were examined and found to be highly defective in the recombination-independent repair of ICLs, while mutants deficient in homologous recombination were found to be proficient. Mutation analysis of plasmids recovered from transfected cells showed frequent base substitutions at or near positions opposing a cross-linked thymidine residue. Based on these results, we suggest a distinct pathway for DNA interstrand cross-link repair involving nucleotide excision repair and a putative lesion bypass mechanism.

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