scholarly journals High-resolution mapping of DNA alkylation damage and base excision repair at yeast transcription factor binding sites

2021 ◽  
Author(s):  
Peng Mao ◽  
Mingrui Duan ◽  
Smitha Sivapragasam ◽  
Jacob S Antony ◽  
Jenna Ulibarri ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Binding Sites ◽  
Excision Repair ◽  
Yeast Cells ◽  
Damage Distribution ◽  
Base Damage ◽  
Core Motif ◽  
Alkylation Damage ◽  
A Genome ◽  
Base Excision

DNA base damage arises frequently in living cells and needs to be removed by base excision repair (BER) to prevent mutagenesis and genome instability. Both the formation and repair of base damage occur in chromatin and are conceivably affected by DNA-binding proteins such as transcription factors (TFs). However, to what extent TF binding affects base damage distribution and BER in cells is unclear. Here, we used a genome-wide damage mapping method, N-methylpurine-sequencing (NMP-seq), to characterize alkylation damage distribution and BER at TF binding sites in yeast cells treated with the alkylating agent methyl methanesulfonate (MMS). Our data shows that alkylation damage formation was mainly suppressed at the binding sites of yeast TFs Abf1 and Reb1, but individual hotspots with elevated damage levels were also found. Additionally, Abf1 and Reb1 binding strongly inhibits BER in vivo and in vitro, causing slow repair both within the core motif and its adjacent DNA. The observed effects are caused by the TF-DNA interaction, because damage formation and BER can be restored by depletion of Abf1 or Reb1 protein from the nucleus. Thus, our data reveal that TF binding significantly modulates alkylation base damage formation and inhibits repair by the BER pathway. The interplay between base damage formation and BER may play an important role in affecting mutation frequency in gene regulatory regions.

Oxidative base damage to DNA: specificity of base excision repair enzymes

2000 ◽  
Vol 462 (2-3) ◽  
pp. 121-128 ◽  
Author(s):  
Jean Cadet ◽  
Anne-Gaëlle Bourdat ◽  
Cédric D'Ham ◽  
Victor Duarte ◽  
Didier Gasparutto ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Base Damage ◽  
Repair Enzymes ◽  
Base Excision ◽  
Dna Specificity ◽  
Oxidative Base Damage

Involvement of two endonuclease III homologs in the base excision repair pathway for the processing of DNA alkylation damage in Saccharomyces cerevisiae

DNA Repair ◽  
2004 ◽  
Vol 3 (1) ◽  
pp. 51-59 ◽  
Author(s):  
Michelle Hanna ◽  
Barbara L Chow ◽  
Natalie J Morey ◽  
Sue Jinks-Robertson ◽  
Paul W Doetsch ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Dna Alkylation ◽  
Repair Pathway ◽  
Base Excision Repair Pathway ◽  
Alkylation Damage ◽  
Endonuclease Iii ◽  
Base Excision

scholarly journals The involvement of nucleotide excision repair proteins in the removal of oxidative DNA damage

2020 ◽  
Vol 48 (20) ◽  
pp. 11227-11243 ◽  
Author(s):  
Namrata Kumar ◽  
Sripriya Raja ◽  
Bennett Van Houten
Keyword(s):  
Nucleotide Excision Repair ◽  
Base Excision Repair ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Base Damage ◽  
The Past ◽  
Nucleotide Excision ◽  
Oxidative Processes ◽  
Repair Pathways ◽  
Base Excision

Abstract The six major mammalian DNA repair pathways were discovered as independent processes, each dedicated to remove specific types of lesions, but the past two decades have brought into focus the significant interplay between these pathways. In particular, several studies have demonstrated that certain proteins of the nucleotide excision repair (NER) and base excision repair (BER) pathways work in a cooperative manner in the removal of oxidative lesions. This review focuses on recent data showing how the NER proteins, XPA, XPC, XPG, CSA, CSB and UV-DDB, work to stimulate known glycosylases involved in the removal of certain forms of base damage resulting from oxidative processes, and also discusses how some oxidative lesions are probably directly repaired through NER. Finally, since many glycosylases are inhibited from working on damage in the context of chromatin, we detail how we believe UV-DDB may be the first responder in altering the structure of damage containing-nucleosomes, allowing access to BER enzymes.

scholarly journals Versatile Cell-Based Assay for Measuring Base Excision Repair of DNA Alkylation Damage

2021 ◽  
Author(s):  
Yong Li ◽  
Peng Mao ◽  
Evelina Y. Basenko ◽  
Zachary Lewis ◽  
Michael Smerdon ◽  
...  
Keyword(s):  
Dna Damage ◽  
Base Excision Repair ◽  
Cultured Cells ◽  
Excision Repair ◽  
Dna Alkylation ◽  
Model Systems ◽  
Environmental Carcinogens ◽  
Alkylation Damage ◽  
Chemotherapy Drugs ◽  
Base Excision

AbstractDNA alkylation damage induced by environmental carcinogens, chemotherapy drugs, or endogenous metabolites plays a central role in mutagenesis, carcinogenesis, and cancer therapy. Base excision repair (BER) is a conserved, front line DNA repair pathway that removes alkylation damage from DNA. The capacity of BER to repair DNA alkylation varies markedly between different cell types and tissues, which correlates with cancer risk and cellular responses to alkylation chemotherapy. The ability to measure cellular rates of alkylation damage repair by the BER pathway is critically important for better understanding of the fundamental processes involved in carcinogenesis, and also to advance development of new therapeutic strategies. Methods for assessing the rates of alkylation damage and repair, especially in human cells, are limited, prone to significant variability due to the unstable nature of some of the alkyl adducts, and often rely on indirect measurements of BER activity. Here, we report a highly reproducible and quantitative, cell-based assay, named alk-BER (alkylation Base Excision Repair) for measuring rates of BER following alkylation DNA damage. The alk-BER assay involves specific detection of methyl DNA adducts (7-methyl guanine and 3-methyl adenine) directly in genomic DNA. The assay has been developed and adapted to measure the activity of BER in fungal model systems and human cell lines. Considering the specificity and conserved nature of BER enzymes, the assay can be adapted to virtually any type of cultured cells. Alk-BER offers a cost efficient and reliable method that can effectively complement existing approaches to advance integrative research on mechanisms of alkylation DNA damage and repair.

The Contribution of DNA Base Damage to Human Cancer Is Modulated by the Base Excision Repair Interaction Network

2008 ◽  
Vol 14 (4) ◽  
pp. 217-273 ◽  
Author(s):  
Katarzyna D. Arczewska ◽  
Katerina Michalickova ◽  
Ian M. Donaldson ◽  
Hilde Nilsen
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Human Cancer ◽  
Interaction Network ◽  
Base Damage ◽  
Dna Base ◽  
Base Excision

scholarly journals The activity of yeast Apn2 AP endonuclease at uracil-derived AP sites is dependent on the major carbon source

2020 ◽  
Author(s):  
Kasey Stokdyk ◽  
Alexandra Berroyer ◽  
Zacharia A. Grami ◽  
Nayun Kim
Keyword(s):  
Carbon Source ◽  
Base Excision Repair ◽  
Glucose Repression ◽  
Excision Repair ◽  
Yeast Cells ◽  
Repair Pathway ◽  
Ap Endonuclease ◽  
Base Excision Repair Pathway ◽  
Ap Sites ◽  
Base Excision

ABSTRACTYeast Apn2 is an AP endonuclease and DNA 3’-diesterase that belongs to the Exo III family with homology to the E. coli exonuclease III, Schizosaccharomyces pombe eth1, and human AP endonucleases APEX1 and APEX2. In the absence of Apn1, the major AP endonuclease in yeast, Apn2 can cleave the DNA backbone at an AP lesion initiating the base excision repair pathway. In order to study the role and relative contribution of Apn2, we took advantage of a reporter system that was previously used to delineate how uracil-derived AP sites are repaired. At this reporter, disruption of the Apn1-initiated base excision repair pathway led to a significant elevation of A:T to C:G transversions. Here we show that such highly elevated A:T to C:G transversion mutations associated with uracil residues in DNA are abolished when apn1Δ yeast cells are grown in glucose as the primary carbon source. We also show that the disruption of Apn2, either by the complete gene deletion or by the mutation of a catalytic residue, results in a similarly reduced rate of the uracil-associated mutations. Overall, our results indicate that Apn2 activity is regulated by the glucose repression pathway in yeast.

A new Schizosaccharomyces pombe base excision repair mutant, nth1, reveals overlapping pathways for repair of DNA base damage

2003 ◽  
Vol 48 (2) ◽  
pp. 465-480 ◽  
Author(s):  
Fekret Osman ◽  
Magnar Bjørås ◽  
Ingrun Alseth ◽  
Ingrid Morland ◽  
S. McCready ◽  
...  
Keyword(s):  
Schizosaccharomyces Pombe ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Base Damage ◽  
Dna Base ◽  
Base Excision

Redox Regulation in the Base Excision Repair Pathway: Old and New Players as Cancer Therapeutic Targets

2020 ◽  
Vol 27 (12) ◽  
pp. 1901-1921 ◽  
Author(s):  
Aleksandra Rajapakse ◽  
Amila Suraweera ◽  
Didier Boucher ◽  
Ali Naqi ◽  
Kenneth O'Byrne ◽  
...  
Keyword(s):  
Dna Damage ◽  
Base Excision Repair ◽  
Oxidative Dna Damage ◽  
Redox Regulation ◽  
Therapeutic Potential ◽  
Excision Repair ◽  
Cellular Transformation ◽  
Enzymatic Reactions ◽  
Base Damage ◽  
Base Excision

Background:Reactive Oxygen Species (ROS) are by-products of normal cellular metabolic processes, such as mitochondrial oxidative phosphorylation. While low levels of ROS are important signalling molecules, high levels of ROS can damage proteins, lipids and DNA. Indeed, oxidative DNA damage is the most frequent type of damage in the mammalian genome and is linked to human pathologies such as cancer and neurodegenerative disorders. Although oxidative DNA damage is cleared predominantly through the Base Excision Repair (BER) pathway, recent evidence suggests that additional pathways such as Nucleotide Excision Repair (NER) and Mismatch Repair (MMR) can also participate in clearance of these lesions. One of the most common forms of oxidative DNA damage is the base damage 8-oxoguanine (8-oxoG), which if left unrepaired may result in G:C to A:T transversions during replication, a common mutagenic feature that can lead to cellular transformation.Objective:Repair of oxidative DNA damage, including 8-oxoG base damage, involves the functional interplay between a number of proteins in a series of enzymatic reactions. This review describes the role and the redox regulation of key proteins involved in the initial stages of BER of 8-oxoG damage, namely Apurinic/Apyrimidinic Endonuclease 1 (APE1), human 8-oxoguanine DNA glycosylase-1 (hOGG1) and human single-stranded DNA binding protein 1 (hSSB1). Moreover, the therapeutic potential and modalities of targeting these key proteins in cancer are discussed.Conclusion:It is becoming increasingly apparent that some DNA repair proteins function in multiple repair pathways. Inhibiting these factors would provide attractive strategies for the development of more effective cancer therapies.

scholarly journals Targeted detection of in vivo endogenous DNA base damage reveals preferential base excision repair in the transcribed strand

2011 ◽  
Vol 40 (1) ◽  
pp. 206-219 ◽  
Author(s):  
António M. C. Reis ◽  
Wilbur K. Mills ◽  
Ilangovan Ramachandran ◽  
Errol C. Friedberg ◽  
David Thompson ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Base Damage ◽  
Dna Base ◽  
Base Excision ◽  
Targeted Detection
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