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Role of Base Excision "Repair" Enzymes in Erasing Epigenetic Marks from DNA.

ABSTRACT: Base excision repair (BER) is one of several DNA repair pathways found in all three domains of life. BER counters the mutagenic and cytotoxic effects of damage that occurs continuously to the nitrogenous bases in DNA, and its critical role in maintaining genomic integrity is well established. However, BER also performs essential functions in processes other than DNA repair, where it acts on naturally modified bases in DNA. A prominent example is the central role of BER in mediating active DNA demethylation, a multistep process that erases the epigenetic mark 5-methylcytosine (5mC), and derivatives thereof, converting them back to cytosine. Herein, we review recent advances in the understanding of how BER mediates this critical component of epigenetic regulation in plants and animals.

SUBMITTER: Drohat AC

PROVIDER: S-EPMC5299066 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Role of Base Excision "Repair" Enzymes in Erasing Epigenetic Marks from DNA.

Drohat Alexander C AC Coey Christopher T CT

Chemical reviews 20160808 20

Base excision repair (BER) is one of several DNA repair pathways found in all three domains of life. BER counters the mutagenic and cytotoxic effects of damage that occurs continuously to the nitrogenous bases in DNA, and its critical role in maintaining genomic integrity is well established. However, BER also performs essential functions in processes other than DNA repair, where it acts on naturally modified bases in DNA. A prominent example is the central role of BER in mediating active DNA de ...[more]

PMID: 27501078

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Oxidative DNA damage is epigenetic by regulating gene transcription via base excision repair.

Project description:Reactive oxygen species (ROS) have emerged as important cellular-signaling agents for cellular survival. Herein, we demonstrate that ROS-mediated oxidation of DNA to yield 8-oxo-7,8-dihydroguanine (OG) in gene promoters is a signaling agent for gene activation. Enhanced gene expression occurs when OG is formed in guanine-rich, potential G-quadruplex-forming sequences (PQS) in promoter-coding strands, initiating base excision repair (BER) by 8-oxoguanine DNA glycosylase (OGG1), yielding an abasic site (AP). The AP enables melting of the duplex to unmask the PQS, adopting a G-quadruplex fold in which apurinic/apyrimidinic endonuclease 1 (APE1) binds, but inefficiently cleaves, the AP for activation of vascular endothelial growth factor (VEGF) or endonuclease III-like protein 1 (NTHL1) genes. These details were mapped via synthesis of OG and AP analogs at single-nucleotide precision within the promoter of a luciferase reporter system. The reporters were analyzed in human and mouse cells while selectively knocking out or down critical BER proteins to identify the impact on luciferase expression. Identification of the oxidatively modified DNA base OG to guide BER activity in a gene promoter and impact cellular phenotype ascribes an epigenetic role to OG.

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Complementation of aprataxin deficiency by base excision repair enzymes.

Project description:Abortive ligation during base excision repair (BER) leads to blocked repair intermediates containing a 5'-adenylated-deoxyribose phosphate (5'-AMP-dRP) group. Aprataxin (APTX) is able to remove the AMP group allowing repair to proceed. Earlier results had indicated that purified DNA polymerase ? (pol ?) removes the entire 5'-AMP-dRP group through its lyase activity and flap endonuclease 1 (FEN1) excises the 5'-AMP-dRP group along with one or two nucleotides. Here, using cell extracts from APTX-deficient cell lines, human Ataxia with Oculomotor Apraxia Type 1 (AOA1) and DT40 chicken B cell, we found that pol ? and FEN1 enzymatic activities were prominent and strong enough to complement APTX deficiency. In addition, pol ?, APTX and FEN1 coordinate with each other in processing of the 5'-adenylated dRP-containing BER intermediate. Finally, other DNA polymerases and a repair factor with dRP lyase activity (pol ?, pol ?, pol ? and Ku70) were found to remove the 5'-adenylated-dRP group from the BER intermediate. However, the activities of these enzymes were weak compared with those of pol ? and FEN1.

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The role of DNA base excision repair in brain homeostasis and disease.

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Isoforms of Base Excision Repair Enzymes Produced by Alternative Splicing.

Project description:Transcripts of many enzymes involved in base excision repair (BER) undergo extensive alternative splicing, but functions of the corresponding alternative splice variants remain largely unexplored. In this review, we cover the studies describing the common alternatively spliced isoforms and disease-associated variants of DNA glycosylases, AP-endonuclease 1, and DNA polymerase beta. We also discuss the roles of alternative splicing in the regulation of their expression, catalytic activities, and intracellular transport.

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8-Oxoguanine DNA glycosylase-1-driven DNA base excision repair: role in asthma pathogenesis.

Project description:To provide both an overview and evidence of the potential cause of oxidative DNA base damage and repair signaling in chronic inflammation and histological changes associated with asthma.Asthma is initiated/maintained by immunological, genetic/epigenetic, and environmental factors. It is a world-wide health problem, as current therapies suppress symptoms rather than prevent/reverse the disease, largely due to gaps in understanding its molecular mechanisms. Inflammation, oxidative stress, and DNA damage are inseparable phenomena, but their molecular roles in asthma pathogenesis are unclear. It was found that among oxidatively modified DNA bases, 8-oxoguanine (8-oxoG) is one of the most abundant, and its levels in DNA and body fluids are considered a biomarker of ongoing asthmatic processes. Free 8-oxoG forms a complex with 8-oxoG DNA glycosylase-1 and activates RAS-family GTPases that induce gene expression to mobilize innate and adaptive immune systems, along with genes regulating airway hyperplasia, hyper-responsiveness, and lung remodeling in atopic and nonatopic asthma.DNA's integrity must be maintained to prevent mutation, so its continuous repair and downstream signaling 'fuel' chronic inflammatory processes in asthma and form the basic mechanism whose elucidation will allow the development of new drug targets for the prevention/reversal of lung diseases.

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Base-excision restriction enzymes: expanding the world of epigenetic immune systems.

Project description:The restriction enzymes examined so far are phosphodiesterases, which cleave DNA strands by hydrolysing phosphodiester bonds. Based on the mobility of restriction-modification systems, recent studies have identified a family of restriction enzymes that excise a base in their recognition sequence to generate an abasic (AP) site unless the base is properly methylated. These restriction glycosylases also show intrinsic but uncoupled AP lyase activity at the AP site, generating an atypical strand break. Action of an AP endonuclease at the AP site may generate another atypical break, rejoining/repairing of which is difficult. This PabI family of restriction enzymes contain a novel fold (HALFPIPE) and show unusual properties, such as non-requirement of divalent cations for cleavage. These enzymes are present in Helicobacteraceae/Campylobacteraceae and in few hyperthermophilic archaeal species. In Helicobacter genomes, their recognition sites are strongly avoided, and the encoding genes are often inactivated by mutations or replacement, indicating that their expression is toxic for the cells. The discovery of restriction glycosylases generalizes the concept of restriction-modification systems to epigenetic immune systems, which may use any mode of damage to DNA that are considered 'non-self' based on epigenetic modifications. This concept will add to our understanding of immunity and epigenetics.

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Role of base excision repair in maintaining the genetic and epigenetic integrity of CpG sites.

Project description:Cytosine methylation at CpG dinucleotides is a central component of epigenetic regulation in vertebrates, and the base excision repair (BER) pathway is important for maintaining both the genetic stability and the methylation status of CpG sites. This perspective focuses on two enzymes that are of particular importance for the genetic and epigenetic integrity of CpG sites, methyl binding domain 4 (MBD4) and thymine DNA glycosylase (TDG). We discuss their capacity for countering C to T mutations at CpG sites, by initiating base excision repair of G · T mismatches generated by deamination of 5-methylcytosine (5mC). We also consider their role in active DNA demethylation, including pathways that are initiated by oxidation and/or deamination of 5mC.

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Direct fluorescence monitoring of DNA base excision repair.

Project description: Not available

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Lamin A/C promotes DNA base excision repair.

Project description:The A-type lamins (lamin A/C), encoded by the LMNA gene, are important structural components of the nuclear lamina. LMNA mutations lead to degenerative disorders known as laminopathies, including the premature aging disease Hutchinson-Gilford progeria syndrome. In addition, altered lamin A/C expression is found in various cancers. Reports indicate that lamin A/C plays a role in DNA double strand break repair, but a role in DNA base excision repair (BER) has not been described. We provide evidence for reduced BER efficiency in lamin A/C-depleted cells (Lmna null MEFs and lamin A/C-knockdown U2OS). The mechanism involves impairment of the APE1 and POLβ BER activities, partly effectuated by associated reduction in poly-ADP-ribose chain formation. Also, Lmna null MEFs displayed reduced expression of several core BER enzymes (PARP1, LIG3 and POLβ). Absence of Lmna led to accumulation of 8-oxoguanine (8-oxoG) lesions, and to an increased frequency of substitution mutations induced by chronic oxidative stress including GC>TA transversions (a fingerprint of 8-oxoG:A mismatches). Collectively, our results provide novel insights into the functional interplay between the nuclear lamina and cellular defenses against oxidative DNA damage, with implications for cancer and aging.

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Base excision repair enzymes protect abasic sites in duplex DNA from interstrand cross-links.

Project description:Hydrolysis of the N-glycosyl bond between a nucleobase and deoxyribose leaves an abasic site within duplex DNA. The abasic site can react with exocyclic amines of nucleobases on the complementary strand to form interstrand DNA-DNA cross-links (ICLs). We find that several enzymes from the base excision repair (BER) pathway protect an abasic site on one strand of a DNA duplex from cross-linking with an amine on the opposing strand. Human alkyladenine DNA glycosylase (AAG) and Escherichia coli 3-methyladenine DNA glycosylase II (AlkA) accomplish this by binding tightly to the abasic site and sequestering it. AAG protects an abasic site opposite T, the product of its canonical glycosylase reaction, by a factor of ?10-fold, as estimated from its inhibition of the reaction of an exogenous amine with the damaged DNA. Human apurinic/apyrimidinic site endonuclease 1 and E. coli endonuclease III both decrease the amount of ICL at equilibrium by generating a single-strand DNA nick at the abasic position as it is liberated from the cross-link. The reversibility of the reaction between amines and abasic sites allows BER enzymes to counter the potentially disruptive effects of this type of cross-link on DNA transactions.

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