Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.1.30.2 (endonuclease)
18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Discovered as a DNA repair protein, Ape1 has been associated with other functions, notably redox regulation of transcription factors (Ref1 activity). Because deletion of the mouse gene produces embryonic lethality and stable Ape1-deficient cell lines have not been reported, there has been uncertainty about a possible vital cellular function of Ape1. We addressed this issue by using RNA interference (RNAi) in several human cell types. Strong downregulation of Ape1 stopped cell proliferation and activated apoptosis, which was correlated with accumulation of abasic DNA damage. These effects were reversed by expression of yeast Apn1 protein, which is structurally unrelated to Ape1 but shares enzymatic activity in repair of abasic sites (AP endonuclease). Because Apn1 would lack Ref1 activity or the protein interactions of Ape1, we conclude that the AP endonuclease activity is essential for cellular viability. Accumulation of abasic DNA damage from intrinsic sources appears sufficient to trigger cell death when Ape1-mediated repair is deficient.
...
PMID:A vital role for Ape1/Ref1 protein in repairing spontaneous DNA damage in human cells. 1569 46

DNA single-strand breaks (SSB) activate poly (ADP-ribose) polymerase 1 (PARP1), which then polymerizes ADP-ribosyl groups on various nuclear proteins, consuming cellular energy. Although PARP1 has a role in repairing SSB, activation of PARP1 also causes necrosis and inflammation due to depletion of cellular energy. Here we show that the major mammalian apurinic/apyrimidinic (AP) endonuclease-1 (APE1), an essential DNA repair protein, binds to SSB and suppresses the activation of PARP1. APE1's high affinity for SSB requires Arg177, which is unique in mammalian APEs. PARP1's binding to the cleaved DNA was inhibited, and PARP1 activation was suppressed by the wild-type APE1, but not by the R177A mutant APE1 protein. Cells transiently transfected with the wild-type APE1 decreased the PARP1 activation after H2O2 treatment, while such suppression did not occur with the expression of the R177A APE1 mutant. These results suggest that APE1 suppresses the activation of PARP1 during the repair process of the DNA damage generated by oxidative stress, which may have an important implication for cells to avoid necrosis due to energy depletion.
...
PMID:The human apurinic/apyrimidinic endonuclease-1 suppresses activation of poly(adp-ribose) polymerase-1 induced by DNA single strand breaks. 1673 Aug 71

Restriction endonuclease BcnI cleaves duplex DNA containing the sequence CC/SGG (S stands for C or G, / designates a cleavage position) to generate staggered products with single nucleotide 5'-overhangs. Here, we show that BcnI functions as a monomer that interacts with its target DNA in 1:1 molar ratio and report crystal structures of BcnI in the absence and in the presence of DNA. In the complex with DNA, BcnI makes specific contacts with all five bases of the target sequence and not just with a half-site, as the protomer of a typical dimeric restriction endonuclease. Our data are inconsistent with BcnI dimerization and suggest that the enzyme introduces double-strand breaks by sequentially nicking individual DNA strands, although this remains to be confirmed by kinetic experiments. BcnI is remotely similar to the DNA repair protein MutH and shares approximately 20% sequence identity with the restriction endonuclease MvaI, which is specific for the related sequence CC/WGG (W stands for A or T). As expected, BcnI is structurally similar to MvaI and recognizes conserved bases in the target sequence similarly but not identically. BcnI has a unique machinery for the recognition of the central base-pair.
...
PMID:Monomeric restriction endonuclease BcnI in the apo form and in an asymmetric complex with target DNA. 1744 30

Human apurinic/apyrimidinic (AP) endonuclease 1 (APE1) is multifunctional enzyme. APEI is involved in the DNA base excision repair process (BER). APE1 participates in BER by cleaving the DNA adjacent to the 5' side of an AP site to produce a hydroxyl group at the 3' terminus of an unmodified nucleotide upstream of the nick and a 5' deoxyribose phosphate moiety downstream. In addition to its AP-endonucleolytic function, APE1 possesses 3' phosphodiesterase, 3'-5' exonuclease and 3' phosphatase activities. Independently of being characterized as DNA repair protein, APE1 was identified as redox-factor (Ref-1). Our own and literature data on the role of APE1 additional functions in cell metabolism and on interactions of APE1 with DNA and other proteins that participate in BER are analyzed in this review.
...
PMID:[Multifunctional human apurinic/apyrimidinic endonuclease 1: the role of additional functions]. 1768 23

The removal of DNA interstrand cross-links (ICLs) has proven to be notoriously complicated due to the involvement of multiple pathways of DNA repair, which include the Fanconi anemia/BRCA pathway, homologous recombination and components of the nucleotide excision and mismatch repair pathways. Members of the SNM1 gene family have also been shown to have a role in mediating cellular resistance to ICLs, although their precise function has remained elusive. Here, we show that knockdown of Snm1B/Apollo in human cells results in hypersensitivity to mitomycin C (MMC), but not to IR. We also show that Snm1B-deficient cells exhibit a defective S phase checkpoint in response to MMC, but not to IR, and this finding may account for the specific sensitivity to the cross-linking drug. Interestingly, although previous studies have largely implicated ATR as the major kinase activated in response to ICLs, we show that it is activation of the ATM-mediated checkpoint that is defective in Snm1B-deficient cells. The requirement for Snm1B in ATM checkpoint activation specifically after ICL damage is correlated with its role in promoting double-strand break formation, and thus replication fork collapse. Consistent with this result Snm1B was found to interact directly with Mus81-Eme1, an endonuclease previously implicated in fork collapse. In addition, we also show that Snm1B interacts with the Mre11-Rad50-Nbs1 (MRN) complex and with FancD2 further substantiating its role as a checkpoint/DNA repair protein.
...
PMID:Snm1B/Apollo mediates replication fork collapse and S Phase checkpoint activation in response to DNA interstrand cross-links. 1846 62

Apurinic/apyrimidinic (AP) endonuclease 1 (Ape1) is an essential DNA repair protein that plays a critical role in repair of AP sites via base excision repair. Ape1 has received attention as a druggable oncotherapeutic target, especially for treating intractable cancers such as glioblastoma. The goal of this study was to identify small-molecule inhibitors of Ape1 AP endonuclease. For this purpose, a fluorescence-based high-throughput assay was used to screen a library of 60,000 small-molecule compounds for ability to inhibit Ape1 AP endonuclease activity. Four compounds with IC(50) values less than 10 microM were identified, validated, and characterized. One of the most promising compounds, designated Ape1 repair inhibitor 03 [2,4,9-trimethylbenzo[b][1,8]-naphthyridin-5-amine; AR03), inhibited cleavage of AP sites in vivo in SF767 glioblastoma cells and in vitro in whole cell extracts and inhibited purified human Ape1 in vitro. AR03 has low affinity for double-stranded DNA and weakly inhibits the Escherichia coli endonuclease IV, requiring a 20-fold higher concentration than for inhibition of Ape1. AR03 also potentiates the cytotoxicity of methyl methanesulfonate and temozolomide in SF767 cells. AR03 is chemically distinct from the previously reported small-molecule inhibitors of Ape1. AR03 is a novel small-molecule inhibitor of Ape1, which may have potential as an oncotherapeutic drug for treating glioblastoma and other cancers.
...
PMID:Novel small-molecule inhibitor of apurinic/apyrimidinic endonuclease 1 blocks proliferation and reduces viability of glioblastoma cells. 2050 14

Apurinic/apyrimidinic endonuclease 1 (APE1) is a DNA repair protein, which plays important roles in the base excision repair (BER) pathway. Genetic variations of APE1 have been shown to influence an individual's susceptibility to carcinogenesis. We hypothesized the genetic polymorphisms of APE1 are associated with the risk of renal cell carcinoma (RCC). In a case-control study of 612 RCC patients and 632 age and sex matched healthy controls, we genotyped two APE1 functional polymorphisms (-656 T>G, rs1760944 and 1349 T>G, rs1130409) and assessed their associations with risk of RCC. We found that, compared with 1349 TT/TG genotypes, the variant genotype 1349 GG had a significantly increased RCC risk [adjusted odds ratio (OR) = 1.47, 95% confidence interval (CI) = 1.10-1.95], particularly among subgroups of BMI > 23 kg/m(2) (OR = 1.54, 95% CI = 1.06-2.22), male (OR = 1.70, 95% CI = 1.17-2.46), never smokers (OR = 1.56, 95% CI = 1.11-2.21), light smokers (OR = 2.01, 95%CI = 1.02-3.95), and drinkers (OR = 2.00, 95% CI = 1.13-3.54). Furthermore, the polymorphism was significantly associated with risk of developing localized stage RCC. No altered RCC risk was associated with the -656 T>G polymorphism, but we found individuals who were homozygous for both risk alleles of the two SNPs had a 2.17-fold increased risk for RCC, compared to individuals with 0 risk alleles. Our results suggest that polymorphisms of APE1 may confer susceptibility to RCC.
...
PMID:Genetic polymorphisms in APE1 are associated with renal cell carcinoma risk in a Chinese population. 2153 78

Structure-specific 5'-nucleases form a superfamily of evolutionarily conserved phosphodiesterases that catalyse a precise incision of a diverse range of DNA and RNA substrates in a sequence-independent manner. Superfamily members, such as flap endonucleases, exonuclease 1, DNA repair protein XPG, endonuclease GEN1 and the 5'-3'-exoribonucleases, play key roles in many cellular processes such as DNA replication and repair, recombination, transcription, RNA turnover and RNA interference. In this review, we discuss recent results that highlight the conserved architectures and active sites of the structure-specific 5'-nucleases. Despite substrate diversity, a common gating mechanism for sequence-independent substrate recognition and incision emerges, whereby double nucleotide unpairing of substrates is required to access the active site.
...
PMID:Unpairing and gating: sequence-independent substrate recognition by FEN superfamily nucleases. 2211 11

Essential meiotic endonuclease 1 homolog 1 (EME1) is a key DNA repair protein that participates in the recognition and repair of DNA double-strand breaks. Deficiency of the EME1 gene can lead to spontaneous genomic instability and thus contribute to tumorgenesis. We hypothesized that the exon variants of EME1 confer genetic susceptibility to breast cancer. In a case-control study of 748 breast cancer patients and 778 normal controls, we analyzed the association between two exon variants of EME1 (i.e.,Ile350Thr: rs12450550T > C and Glu69Asp: rs3760413T > G) and breast cancer risk. We found that compared to the common Ile/Ile genotype, the Thr variant genotypes (Thr/Ile + Thr/Thr) conferred a 1.47-fold increased risk of breast cancer (OR=1.47, 95% CI=1.13-1.92). The variant Ile350Thr was also associated with early onset of breast cancer (r = -0.116, P = 0.002). The mean age of onset was 44.4 years for Thr/Thr genotype carriers and 46.5 years for Thr/Ile genotype carriers, which was significantly lower than that (49.4 years) for Ile/Ile genotype carriers (P = 0.006). Moreover, no significant association was observed between the Glu69Asp variant and breast cancer risk. Our findings suggest that the EME1 variant Ile350Thr contributes to an increased risk and early onset of breast cancer.
...
PMID:Effect of EME1 exon variant Ile350Thr on risk and early onset of breast cancer in southern Chinese women. 2372 Jun 74

Unless repaired, DNA damage can drive mutagenesis or cell death. DNA repair proteins may therefore be used as biomarkers in disease etiology or therapeutic response prediction. Thus, the accurate determination of DNA repair protein expression and genotype is of fundamental importance. Among DNA repair proteins involved in base excision repair, apurinic/apyrimidinic endonuclease 1 (APE1) is the major endonuclease in mammals and plays important roles in transcriptional regulation and modulating stress responses. Here, we present a novel approach involving LC-MS/MS with isotope-dilution to positively identify and accurately quantify APE1 in human cells and mouse tissue. A completely (15)N-labeled full-length human APE1 was produced and used as an internal standard. Fourteen tryptic peptides of both human APE1 (hAPE1) and (15)N-labeled hAPE1 were identified following trypsin digestion. These peptides matched the theoretical peptides expected from trypsin digestion and provided a statistically significant protein score that would unequivocally identify hAPE1. Using the developed methodology, APE1 was positively identified and quantified in nuclear and cytoplasmic extracts of multiple human cell lines and mouse liver using selected-reaction monitoring of typical mass transitions of the tryptic peptides. We also show that the methodology can be applied to the identification of hAPE1 variants found in the human population. The results describe a novel approach for the accurate measurement of wild-type and variant forms of hAPE1 in vivo, and ultimately for defining the role of this protein in disease development and treatment responses.
...
PMID:Identification and quantification of DNA repair protein apurinic/apyrimidinic endonuclease 1 (APE1) in human cells by liquid chromatography/isotope-dilution tandem mass spectrometry. 2392 45


<< Previous 1 2 3 Next >>

---