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

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

Hypoxia-inducible factor 1alpha (HIF-1alpha) functions as a transcription factor that is activated by decreased cellular oxygen concentrations to induce expression of a network of genes involved in angiogenesis, erythropoiesis, and glucose homeostasis. Here we demonstrate that two members of the SRC-1/p160 family of transcriptional coactivators harboring histone acetyltransferase activity, SRC-1 and transcription intermediary factor 2 (TIF2), are able to interact with HIF-1alpha and enhance its transactivation potential in a hypoxia-dependent manner. HIF-1alpha contains within its C terminus two transactivation domains. The hypoxia-inducible activity of both these domains was enhanced by either SRC-1 or the CREB-binding protein (CBP)/p300 coactivator. Moreover, at limiting concentrations, SRC-1 produced this effect in synergy with CBP. Interestingly, this effect was strongly potentiated by the redox regulatory protein Ref-1, a dual-function protein harboring DNA repair endonuclease and cysteine reducing activities. These data indicate that all three proteins, CBP, SRC-1, and Ref-1, are important components of the hypoxia signaling pathway and have a common function in regulation of HIF-1alpha function in hypoxic cells. Given the absence of cysteine residues in one of the Ref-1-regulated transactivation domains of HIF-1alpha, it is thus possible that Ref-1 functions in hypoxic cells by targeting critical steps in the recruitment of the CBP-SRC-1 coactivator complex.
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PMID:Redox-regulated recruitment of the transcriptional coactivators CREB-binding protein and SRC-1 to hypoxia-inducible factor 1alpha. 1059 42

DNA repair in chromatin is subject to topological constraints, suggesting a requirement for chromatin modification and remodeling activities. Thymine DNA glycosylase (TDG) initiates repair of G/T and G/U mismatches, commonly associated with CpG islands, by removing thymine and uracil moieties. We report that TDG associates with transcriptional coactivators CBP and p300 and that the resulting complexes are competent for both the excision step of repair and histone acetylation. Furthermore, TDG stimulates CBP transcriptional activity in transfected cells and reciprocally serves as a substrate for CBP/p300 acetylation. Remarkably, this acetylation triggers release of CBP from DNA ternary complexes and also regulates recruitment of repair endonuclease APE. These observations reveal a potential regulatory role for protein acetylation in base mismatch repair and a role for CBP/p300 in maintaining genomic stability.
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PMID:Association of CBP/p300 acetylase and thymine DNA glycosylase links DNA repair and transcription. 1186 1

A putative oncogene bcl-3 was originally identified and cloned at the breakpoint in the recurring chromosome translocation t(14;19) found in some cases of B cell chronic lymphocytic leukemia. Studies of bcl-3-deficient mice demonstrated a critical role for bcl-3 in the development of a normal immune response and the formation of germinal centers in secondary lymphoid organs. However, the molecular mechanism that underlies B cell leukemogenesis and the knockout mouse phenotype remains unclear. Here we have identified and characterized BCL-3-binding protein (B3BP) as a protein interacting specifically with the bcl-3 gene product (BCL-3) by a yeast two-hybrid screen. We found that B3BP associates with not only BCL-3 but also p300/CBP histone acetyltransferases. The N-terminal region of B3BP that contains the ATP-binding site is important for the interaction with BCL-3 and p300/CBP. Homology searches indicate that the ATP-binding region of B3BP, which contains a typical Walker-type ATP-binding P-loop, most resembles that of 2',3'-cyclic nucleotide 3'-phosphodiesterase of mammals and polynucleotide kinase of T4 bacteriophage. In fact B3BP shows intrinsic ATP binding and hydrolyzing activity. Furthermore, we demonstrated that B3BP is a 5'-polynucleotide kinase. We also found a small MutS-related domain, which is thought to be involved in the DNA repair or recombination reaction, in the C-terminal region of B3BP, and it shows nicking endonuclease activity. These observations might help to gain new insights into the function of BCL-3 and p300/CBP, especially the coupling of transcription with repair or recombination.
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PMID:Identification and characterization of BCL-3-binding protein: implications for transcription and DNA repair or recombination. 1273 Jan 95

The human AP-endonuclease (APE1/Ref-1), a multifunctional protein central to repairing abasic sites and single-strand breaks in DNA, also plays a role in transcriptional regulation. Besides activating some transcription factors, APE1 is directly involved in Ca2+-dependent downregulation of parathyroid hormone (PTH) expression by binding to negative calcium response elements (nCaREs) present in the PTH promoter. Here we show that APE1 is acetylated both in vivo and in vitro by the transcriptional co-activator p300 which is activated by Ca2+. Acetylation at Lys6 or Lys7 enhances binding of APE1 to nCaRE. APE1 stably interacts with class I histone deacetylases (HDACs) in vivo. An increase in extracellular calcium enhances the level of acetylated APE1 which acts as a repressor for the PTH promoter. Moreover, chromatin immunoprecipitation (ChIP) assay revealed that acetylation of APE1 enhanced binding of the APE1-HDACs complex to the PTH promoter. These results indicate that acetylation of APE1 plays an important role in this key repair protein's action in transcriptional regulation.
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PMID:Role of acetylated human AP-endonuclease (APE1/Ref-1) in regulation of the parathyroid hormone gene. 1463 89

The human 8-oxoguanine-DNA glycosylase 1 (OGG1) is the major DNA glycosylase responsible for repair of 7,8-dihydro-8-oxoguanine (8-oxoG) and ring-opened fapyguanine, critical mutagenic DNA lesions that are induced by reactive oxygen species. Here we show that OGG1 is acetylated by p300 in vivo predominantly at Lys338/Lys341. About 20% of OGG1 is present in acetylated form in HeLa cells. Acetylation significantly increases OGG1's activity in vitro in the presence of AP-endonuclease by reducing its affinity for the abasic (AP) site product. The enhanced rate of repair of 8-oxoG in the genome by wild-type OGG1 but not the K338R/K341R mutant, ectopically expressed in oxidatively stressed OGG1-null mouse embryonic fibroblasts, suggests that acetylation increases OGG1 activity in vivo. At the same time, acetylation of OGG1 was increased by about 2.5-fold after oxidative stress with no change at the polypeptide level. OGG1 interacts with class I histone deacetylases, which may be responsible for its deacetylation. Based on these results, we propose a novel regulatory function of OGG1 acetylation in repair of its substrates in oxidatively stressed cells.
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PMID:Acetylation of human 8-oxoguanine-DNA glycosylase by p300 and its role in 8-oxoguanine repair in vivo. 1647 87

Flap endonuclease-1 (FEN1) is a structure specific endonuclease. The natural substrates of FEN1 are 5'-flap structures formed by three DNA chains one of them has unannealed flapped 5'-end (flap). Flap structures are the intermediates of different processes of DNA metabolism, such as DNA recombination, Okazaki fragment maturation during replication of lagging strand, as well as strand displacement DNA synthesis in base excision repair. FEN1 also possesses 5'-exonuclease activity and newly discovered gap endonuclease activity. FEN1 is known to interact physically and functionally with a number of DNA replication and repair proteins such as the proliferating cell nuclear antigen, helicase/nuclease Dna2, WRN and BLM proteins, replication protein A, apurinic/apyrimidinic endonuclease 1, DNA polymerase beta, poly(ADP-riboso) polymerase 1, high mobility group protein 1, integrase of human immunodeficiency virus, transcription coactivator p300, chromatin proteins, cyclin-dependent kinases (Cdk1, Cdk2, Cyclin A). FEN1 activity is significant for maintaining the integrity of repeat sequences in genome. Recent data suppose the correlation between the abnormality of hFEN1 activity and arising/progression of neurodegenerative and cancer diseases. FEN1 has the dramatic effect on cell growth and development thereby attracting the interest to this enzyme.
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PMID:[Flap endonuclease-1 and its role in the processes of DNA metabolism in eucaryotic cells]. 1870 99

The mammalian AP-endonuclease (APE1/Ref-1) plays a central role in the repair of oxidized and alkylated bases in mammalian genomes via the base excision repair (BER) pathway. However, APE1, unlike its E. coli prototype Xth, has two unique and apparently distinct transcriptional regulatory activities. APE1 functions as a redox effector factor (Ref-1) for several transcription factors including AP-1, HIF1-alpha, and p53. APE1 was also identified as a direct trans-acting factor for repressing human parathyroid hormone (PTH) and renin genes by binding to the negative calcium-response element (nCaRE) in their promoters. We have characterized APE1's post-translational modification, namely, acetylation which modulates its transcriptional regulatory function. Furthermore, stable interaction of APE1 with several other trans-acting factors including HIF-1alpha, STAT3, YB-1, HDAC1, and CBP/p300 and formation of distinct trans-acting complexes support APE1's direct regulatory function for diverse genes. Multiple functions of mammalian APE1, both in DNA repair and gene regulation, warrant extensive analysis of its own regulation and dissection of the mechanisms. In this review, we have discussed APE1's own regulation and its role as a transcriptional coactivator or corepressor by both redox-dependent and redox-independent (acetylation-mediated) mechanisms, and explore the potential utility of targeting these functions for enhancing drug sensitivity of cancer cells.
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PMID:Transcriptional regulatory functions of mammalian AP-endonuclease (APE1/Ref-1), an essential multifunctional protein. 1871 44

Flap endonuclease 1 (FEN1) and Dna2 endonuclease/helicase (Dna2) sequentially coordinate their nuclease activities for efficient resolution of flap structures that are created during the maturation of Okazaki fragments and repair of DNA damage. Acetylation of FEN1 by p300 inhibits its endonuclease activity, impairing flap cleavage, a seemingly undesirable effect. We now show that p300 also acetylates Dna2, stimulating its 5'-3' endonuclease, the 5'-3' helicase, and DNA-dependent ATPase activities. Furthermore, acetylated Dna2 binds its DNA substrates with higher affinity. Differential regulation of the activities of the two endonucleases by p300 indicates a mechanism in which the acetylase promotes formation of longer flaps in the cell at the same time as ensuring correct processing. Intentional formation of longer flaps mediated by p300 in an active chromatin environment would increase the resynthesis patch size, providing increased opportunity for incorrect nucleotide removal during DNA replication and damaged nucleotide removal during DNA repair. For example, altering the ratio between short and long flap Okazaki fragment processing would be a mechanism for better correction of the error-prone synthesis catalyzed by DNA polymerase alpha.
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PMID:Acetylation of Dna2 endonuclease/helicase and flap endonuclease 1 by p300 promotes DNA stability by creating long flap intermediates. 2001 87

The overexpression of human apurinic/apyrimidinic (AP) endonuclease 1 (APE1/Ref-1), a key enzyme in the DNA base excision repair (BER) pathway, is often associated with tumor cell resistance to various anticancer drugs. In this study, we examined the molecular basis of transcriptional regulatory (nonrepair) function of APE1 in promoting resistance to certain types of drugs. We have recently shown that APE1 stably interacts with Y-box-binding protein 1 (YB-1), and acts as its coactivator for the expression of multidrug resistance gene MDR1, thereby causing drug resistance. In this study, we show, to the best of our knowledge, for the first time that APE1 is stably associated with the basic transcription factor RNA polymerase II (RNA pol II) and the coactivator p300 on the endogenous MDR1 promoter. The depletion of APE1 significantly reduces YB-1-p300 recruitment to the promoter, resulting in reduced RNA pol II loading. Drug-induced APE1 acetylation, which is mediated by p300, enhances formation of acetylated APE1 (AcAPE1)-YB-1-p300 complex on the MDR1 promoter. Enhanced recruitment of this complex increases MDR1 promoter-dependent luciferase activity and its endogenous expression. Using APE1-downregulated cells and cells overexpressing wild-type APE1 or its nonacetylable mutant, we have demonstrated that the loss of APE1's acetylation impaired MDR1 activation and sensitizes the cells to cisplatin or etoposide. We have thus established the basis for APE1's acetylation-dependent regulatory function in inducing MDR1-mediated drug resistance.
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PMID:Human AP endonuclease (APE1/Ref-1) and its acetylation regulate YB-1-p300 recruitment and RNA polymerase II loading in the drug-induced activation of multidrug resistance gene MDR1. 2085 96

Nucleotide excision repair (NER) is an important DNA repair mechanism through which cells remove bulky DNA lesions. Following DNA damage, the histone acetyltransferase (HAT) p300 (also referred to as lysine acetyltransferase or KAT) is known to associate with proliferating cell nuclear antigen (PCNA), a master regulator of DNA replication and repair processes. This interaction, which results in HAT inhibition, may be dissociated by the cell cycle inhibitor p21(CDKN1A), thereby restoring p300 activity; however, the role of this protein interplay is still unclear. Here, we report that silencing p300 or its homolog CREB-binding protein (CBP) by RNA interference (RNAi) significantly reduces DNA repair synthesis in human fibroblasts. In addition, we determined whether p300 and CBP may associate with and acetylate specific NER factors such as XPG, the 3'-endonuclease that is involved in the incision/excision step and is known to interact with PCNA. Our results show that p300 and CBP interact with XPG, which has been found to be acetylated in vivo. XPG is acetylated by p300 in vitro, and this reaction is inhibited by PCNA. Knocking down both p300/CBP by RNAi or by chemical inhibition with curcumin greatly reduced XPG acetylation, and a concomitant accumulation of the protein at DNA damage sites was observed. The ability of p21 to bind PCNA was found to regulate the interaction between p300 and XPG, and an abnormal accumulation of XPG at DNA damage sites was also found in p21(-/-) fibroblasts. These results indicate an additional function of p300/CBP in NER through the acetylation of XPG protein in a PCNA-p21 dependent manner.
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PMID:p300/CBP acetyl transferases interact with and acetylate the nucleotide excision repair factor XPG. 2295 86


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