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  • enzyme
  • DNA-(apurinic or apyrimidinic site) lyase is an enzyme that in humans is encoded by the APEX1 gene. (wikipedia.org)
  • Poly (ADP-ribose) polymerase 1 (PARP1) is an ADP-ribosylating enzyme essential for initiating various forms of DNA repair. (mdpi.com)
  • Inhibiting its enzyme activity with small molecules thus achieves synthetic lethality by preventing unwanted DNA repair in the treatment of cancers. (mdpi.com)
  • Besides presenting current findings on how each process is individually controlled by PARP1, we shall discuss how transcription and DNA repair are so intricately linked that disturbance by PARP1 enzymatic inhibition, enzyme hyperactivation in diseases, and viral replication can favor one function while suppressing the other. (mdpi.com)
  • Poly (ADP-ribose) polymerase 1 (PARP1) is well known as an ADP-ribosylating enzyme, which becomes activated upon binding to DNA single-strand and double-strand breaks (ssDB and dsDB respectively) [ 1 , 2 , 3 , 4 , 5 , 6 ]. (mdpi.com)
  • As an enzyme, PARP1 acts on chromatin remodeling complexes to control DNA accessibility for RNA polymerase [ 18 , 19 , 20 , 21 , 22 ]. (mdpi.com)
  • In the 1970s, this class of enzyme was found to repair at apurinic or apyrimidinic DNA sites in E. coli and in mammalian cells. (wikipedia.org)
  • Since DNA AP lyase is a class of structures who have numerous target genes that encode for different variations of the enzyme, there is no one single enzyme structure that can be used as an example that encompasses all versions of the enzyme. (wikipedia.org)
  • Furthermore, the catalytic mechanism of AP lyases, the β-elimination reaction, proceeds through an imine enzyme-DNA intermediate. (wikipedia.org)
  • Phage-T4 UV endonucleases also catalyze the reaction of the δ-reaction, nicking C5'-O-P bond at AP sites, although this reaction is slow and the enzyme should still be classified as AP lyase. (wikipedia.org)
  • DNA repair enzyme that incises DNA at 8-oxoG residues. (uniprot.org)
  • The primary function of the MUTYH gene is the production of the glycosylase enzyme which catalyzes the removal of 8-0x0G (also 8-oxo-7,8-dihydro-2'-deoxyguanosine, 8-Oxoguanine), the result of base pair transversion. (wikipedia.org)
  • The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a major oxidatively damaged DNA lesion. (wikipedia.org)
  • When an insertion of one nucleotide occurs, the enzyme AP endonuclease (APEX/APE1) cuts out the mismatched base pairs at the AP site and this causes the evolvement of 5'dRP (5' deoxyribose phosphate), a terminal blocking group, and 3'-OH ( 3' hydroxyl end). (wikipedia.org)
  • This structure revealed that the enzyme flips the damaged base out of the double helix into an active site pocket in order to excise it. (wikipedia.org)
  • The APE1 enzyme creates a nick in the phosphodiester backbone at an abasic (baseless) site through a simple acyl substitution mechanism. (wikipedia.org)
  • Both also contain lots of H-bond acceptors which may interact with the H-bond donors in the active site of APE1, causing these inhibitors to stick in the active site and preventing the enzyme from catalyzing other reactions. (wikipedia.org)
  • DNA ligase 1 is an enzyme that in humans is encoded by the LIG1 gene. (wikipedia.org)
  • Previously it had been known that DNA replication occurred through the breakage of the double DNA strand, but the mechanism of action and enzyme responsible for ligating the strands back together was unknown. (wikipedia.org)
  • The LIG1 gene encodes a, 120kDa enzyme, 919 residues long, known as DNA ligase I. The DNA ligase I polypeptide contains an N-terminal replication factory-targeting sequence (RFTS), followed by a nuclear localization sequence (NLS), and three functional domains. (wikipedia.org)
  • In order to ligate these fragments together, the ligase progresses through three steps: Addition of an adenosine monophosphate (AMP) group to the enzyme, referred to as adenylylation, Adenosine monophosphate transfer to the DNA and Nick sealing, or phosphodiester bond formation. (wikipedia.org)
  • pathway
  • BER is the major repair pathway of DNA damage induced by RONs and is critical for maintaining genome stability during chronic inflammation and/or bacterial infection [ 18 ]. (jcancer.org)
  • This pathway involves an enzymatic cascade: following removal of the damaged base by a glycosylase, the damage site is treated by an apurinic/apyrimidinic lyase, and then patched by a polymerase. (jbsdonline.com)
  • The short patch repair pathway employs POLB (DNA polymerase beta), APE1, XRCC1, PARP1 with the addition of either the LIG1 or LIG3 genes. (wikipedia.org)
  • The purpose of PARP1 and XRCC1 in the single strand break repair pathway, is to stabilize the strands of DNA while they undergo repair, synthesis, gap-filling and ligation. (wikipedia.org)
  • Not only is APE1 needed in and of itself to create the nick in the DNA backbone so that the enzymes involved later in the BER pathway can recognize the AP-site, it also has a redox function that helps activate other enzymes involved in DNA repair. (wikipedia.org)
  • While human cells utilize both short- and long-patch BER, the yeast Saccharomyces cerevisiae was long thought to lack a short-patch pathway because it does not have homologs of several mammalian short-patch proteins, including pol β, DNA ligase III, XRCC1, and the kinase domain of PNKP. (wikipedia.org)
  • strand
  • Mammalian cells require non-homologous end joining (NHEJ) for the efficient repair of chromosomal DNA double-strand breaks. (nih.gov)
  • A key feature of biological sources of strand breaks is associated nucleotide damage, including base loss (abasic or apurinic/apyrimidinic (AP) sites). (nih.gov)
  • We show by using cell extracts that Ku is essential for the efficient removal of AP sites near double-strand breaks and, consistent with this result, that joining of such breaks is specifically decreased in cells complemented with a lyase-attenuated Ku mutant. (nih.gov)
  • The nick sealing of the strands is accomplished by the formation of LIG1 (DNA ligase 1) and/or LIG3/ XRCCI complex that attach to processed end of the corrected strands and reinstate the original conformation of the strand. (wikipedia.org)
  • It is hypothesized that Polymerase 𝜹 (POLD) and Polymerase 𝛆 (POLE), assisted by the PCNA (proliferating cell nuclear antigen) in conjunction with replication factor C (RFC) that acts as a stabilizer and places newly synthesized nucleotides on the DNA strand. (wikipedia.org)
  • Both the polymerases repair the DNA by employing the strand displacement synthesis mechanism. (wikipedia.org)
  • FEN1 ( flap structure-specific endonuclease 1), a nuclease, removes the displaced strand and this results in a ligatable strand of DNA.Long patch repair, like short patch repair, includes the use of APE1 and PARP1 and LIG1. (wikipedia.org)
  • Other notable interactions include MUTYH and Replication protein A is a single strand binding protein that prevents the annealing of DNA during replication, it also plays a role as an activator for damage repair on DNA. (wikipedia.org)
  • Both mechanisms form a single-strand break, which is then repaired by either short-patch or long-patch base excision repair. (wikipedia.org)
  • Three APE1 residues (Arg73, Ala74, and Lys78) contact three consecutive DNA phosphates on the strand opposite the one containing the AP site while Tyr128 and Gly127 span and widen the minor groove, anchoring the DNA for the extreme kinking caused by the interaction between positive residues found in four loops and one α-helix and the negative phosphate groups found in the phosphodiester backbone of DNA. (wikipedia.org)
  • To be specific, HMGA2-high cancers display an abnormally strong response to double strand breaks in DNA caused by radiation therapy and some forms of chemotherapy. (wikipedia.org)
  • In order for ligation to occur, a DNA strand break must have a hydroxyl on its 3' end and a phosphate on its 5' end. (wikipedia.org)
  • DNA ligase 1 is responsible for joining Okazaki fragments formed during discontinuous DNA synthesis on the DNA's lagging strand after DNA polymerase δ has replaced the RNA primer nucleotides with DNA nucleotides. (wikipedia.org)
  • If the Okazaki fragments are not properly ligated together, the unligated DNA (containing a 'nick') could easily degrade to a double strand break, a phenomenon known to cause genetic mutations. (wikipedia.org)
  • lesion
  • The nucleosome presents a particular challenge to BER enzymes: the rate and efficiency of repair at a particular lesion site are expected to depend on the relative rotational and translational position of the lesion site on the histone core. (jbsdonline.com)
  • Here, we examine the rate and efficiency of the removal of 8-oxo-7,8-dihydroguanine (8-oxoG), the predominant oxidative lesion in DNA (Michaels & Miller, 1992), by the glycosylase hOGG1 as a function of position within the nucleosome. (jbsdonline.com)
  • gene
  • In this review article, we will discuss how dysbiotic microbiota induce DNA damage, its impact on base excision repair capacity, the potential link of host BER gene polymorphism, and the risk of dysbiotic microbiota mediated genomic instability and colon cancer. (jcancer.org)
  • Functional dissection of siRNA sequence by systematic DNA substitution: modified siRNA with a DNA seed arm is a powerful tool for mammalian gene silencing with significantly reduced off-target effect. (abnova.com)
  • APE1 is a gene that codes for DNA AP lyase in humans which binds to AP DNA loops into both the DNA major and minor grooves and binds a flipped-out AP site in a pocket that excludes DNA bases and racemized-anomer AP sites. (wikipedia.org)
  • There is an helix-hairpin-helix and pseudo helix-hairpin-helix contained within the N-terminal, in addition to and iron cluster motif The BER (base excision repair) employed by the gene is the result of a collaborative effort by both MUTYH and OGG1. (wikipedia.org)
  • mutagenic
  • Involved in base excision repair of DNA damaged by oxidation or by mutagenic agents. (string-db.org)
  • The critical role of PARP1 in DNA repair is reflected by its frequent upregulation in cancer [ 8 , 9 ], as well as the hypersensitivity of PARP1 null animals towards the mutagenic effects of DNA damaging agents [ 10 ]. (mdpi.com)
  • These gap sites are mutagenic in nature and require constant and immediate emendation and this is achieved by the active involvement of protein complexes that repair the AP gap site via short and long patch repair pathways. (wikipedia.org)
  • zinc
  • The N-terminal catalytic domain and the C-terminal zinc finger straddle the DNA with the long axis of the protein oriented roughly orthogonal to the helical axis of the DNA. (wikipedia.org)
  • Residues that contact DNA are located in the catalytic domain and in a beta-hairpin loop formed by the zinc finger. (wikipedia.org)
  • mechanism
  • Both the APE1 active-site geometry and a complex with cleaved AP-DNA and Mn2+ support a testable structure-based catalytic mechanism. (wikipedia.org)
  • Base excision repair is the mechanism by which damaged bases in DNA are removed and replaced. (wikipedia.org)
  • There are four types of AP endonucleases that have been classified according to their mechanism and site of incision. (wikipedia.org)
  • Class II AP endonucleases incise DNA 5' to AP sites by a hydrolytic mechanism, leaving a 3'-hydroxyl and a 5'-deoxyribose phosphate residue. (wikipedia.org)
  • Artificial addition of HMGA2 to some forms of cancer unresponsive to DNA damage cause them to respond to the treatment instead, although the mechanism by which this phenomenon occurs is also not understood. (wikipedia.org)
  • In biochemistry and genetics, base excision repair (BER) is a cellular mechanism that repairs damaged DNA throughout the cell cycle. (wikipedia.org)
  • In the 1960s Lehman laboratories investigated this mystery, discovering DNA ligase and its mechanism of action in 1967. (wikipedia.org)
  • Residues
  • Hydrolysis of DNA containing ring-opened 7-methylguanine residues, releasing 2,6-diamino-4-hydroxy-5-(N-methyl)formamidopyrimidine. (uniprot.org)
  • APE1 contains several amino acid residues that enable it to react selectively with AP sites. (wikipedia.org)
  • substrate
  • Recovered DNA was then assessed for efficiencies of substrate recovery and joining by qPCRs using substrate and junction primer pairs, respectively. (nih.gov)
  • b , Addition of NaBH 4 at the start of the reaction reduces the Schiff base covalent intermediate, forming a stable adduct between an abasic site within a radiolabeled DNA substrate and the 5'dPR/AP lyase. (nih.gov)
  • SMUG1 prefers single-stranded DNA as substrate, but also removes U from double-stranded DNA. (wikipedia.org)
  • genomic
  • Oxidized DNA base lesions are removed by base excision repair (BER), however, the role of this altered function of BER, as well as microbiota-mediated genomic instability and colon cancer development, is still poorly understood. (jcancer.org)
  • In eukaryotic cells, short stretches (146 base pairs) of genomic DNA are wrapped around octameric clusters of histone proteins, forming macromolecular structures called nucleosomes (Eickbush & Moudrianakis, 1978). (jbsdonline.com)
  • Genomic_DNA. (genome.jp)
  • protein
  • Top panel shows purified heterodimers, while bottom panel shows phosphorimage of corresponding protein-DNA adducts. (nih.gov)
  • A particular allele of smc6 (smc6-74) is suppressed by overexpression of Brc1, a six-BRCT domain protein that is required for DNA repair during S-phase. (sussex.ac.uk)
  • This protein contains structural DNA-binding domains and may act as a transcriptional regulating factor. (wikipedia.org)
  • HMGA2 contains three basic DNA-binding domains (AT-hooks) that cause the protein to bind to adenine-thymine (AT)-rich regions of nuclear DNA. (wikipedia.org)
  • HMGA2 does not directly promote or inhibit the transcription of any genes, but alters the structure of DNA and promotes the assembly of protein complexes that do regulate the transcription of genes. (wikipedia.org)
  • ligase
  • DNA ligase I is found in eukaryotes and therefore is in the family of ATP-dependent DNA ligases. (wikipedia.org)
  • Activation and recruitment of DNA Ligase I seem to be associated with posttranslational modifications. (wikipedia.org)
  • Eukaryotic DNA ligase 1 catalyzes a reaction that is chemically universal to all ligases. (wikipedia.org)
  • During adenylylation, there is a nucleophilic attack on the alpha phosphate of ATP from a catalytic lysine resulting in the production of inorganic pyrophosphate (PPi) and a covalently bound lysine-AMP intermediate in the active site of DNA ligase 1. (wikipedia.org)
  • During the AMP transfer step, the DNA ligase becomes associated with the DNA, locates a nick and catalyzes a reaction at the 5' phosphate site of the DNA nick. (wikipedia.org)
  • damage
  • Chronic inflammation may promote the release of reactive oxygen and nitrogen species (RONs) that are thought to damage DNA. (jcancer.org)
  • These kinds of DNA damage can be repaired by a variety of DNA repair mechanisms including base excision repair (BER) [ 14 - 16 ]. (jcancer.org)
  • BER repair systems are thought to play a significant role in survival and adaptation of microbiota, repair of microbiota, or bacterial pathogen induced DNA damage [ 17 ]. (jcancer.org)
  • Further, the Apn2 endonuclease is required for the viability of smc6 mutants without extrinsic DNA damage, although this is not due to a defect in base excision repair. (sussex.ac.uk)
  • DNA damage is ubiquitous amongst all forms of life. (wikipedia.org)
  • When left unrepaired, DNA damage can lead to mutagenesis and carcinogenesis. (jbsdonline.com)
  • Organisms have evolved to repair DNA damage through several pathways, including the removal and replacement of damaged DNA bases via base excision repair (BER). (jbsdonline.com)
  • Wilson, N. & Delaney, S. (2009) Structure-Dependent DNA Damage and Repair in a Trinucleotide Repeat Sequence. (jbsdonline.com)
  • 5'dRP
  • b , Radiolabeled 250 bp substrates were incubated with purified Ku, DNA-PKcs, XRCC4-LigaseIV, and XLF at 37°C for 20 minutes (5'dRP-EJ) or 60 minutes (AP-EJ) and products detected by electrophoresis and phosphorimaging. (nih.gov)
  • intermediate
  • FT ACT_SITE 2 2 Schiff-base intermediate with DNA. (genome.jp)
  • An anionic oxygen on the 5' phosphate of the DNA nick serves as the nucleophile, attacking the alpha phosphate of the covalently bound AMP causing the AMP to be covalently bound intermediate (DNA-AMP intermediate). (wikipedia.org)
  • phosphate
  • The C-O-P bond 3' to the apurinic or apyrimidinic site in DNA is broken by a beta-elimination reaction, leaving a 3'-terminal unsaturated sugar and a product with a terminal 5'-phosphate. (uniprot.org)
  • The AP site is then further stabilized through hydrogen bonding of the phosphate group 5´ to the AP site with Asn174, Asn212, His309, and the Mg2+ ion while its orphan base partner is stabilized through hydrogen bonding with Met270. (wikipedia.org)
  • The phosphate group 3' to the AP site is stabilized through hydrogen bonding to Arg177. (wikipedia.org)
  • First, the Asp210 residue in the active site deprotonates a water molecule, which can then perform a nucleophilic attack on the phosphate group located 5´ to the AP site. (wikipedia.org)
  • Next, electrons from one of the oxygen atom in the phosphate group moves down, kicking off one of the other oxygen to create a free 5´ phosphate group on the AP site and a free 3´-OH on the normal nucleotide, both of which are stabilized by the Mg2+ ion. (wikipedia.org)