Disease relevance of HAP1

• Nuclear localization of human AP endonuclease 1 (HAP1/Ref-1) associates with prognosis in early operable non-small cell lung cancer (NSCLC) [1].
• Human AP endonuclease 1 (HAP1) protein expression in breast cancer correlates with lymph node status and angiogenesis [2].
• The HAP1 protein consists of a core domain, which is highly conserved in a family of prokaryotic and eukaryotic DNA repair enzymes, and a 61-amino-acid N-terminal domain absent from bacterial homologs such as Escherichia coli exonuclease III [3].
• The possible involvement of a depletion of cellular glutathione being linked to the hypoxic stress-sensitive phenotype of the antisense HAP1 transfectants came from the finding that they also exhibited hypersensitivity to buthionine sulphoximine, an inhibitor of glutathione biosynthesis [4].
• This report details the crystal structures of icosahedral HBV capsids with and without HAP1 [5].

Psychiatry related information on HAP1

• Hypothalamic huntingtin-associated protein 1 as a mediator of feeding behavior [6].
• Interestingly, [6,6']bibenzothiazolyl-2,2'-diamine, an agent found previously to disrupt aggregates of huntingtin associated with Huntington's disease, can dissociate lithostathine bundles into individual protofilaments [7].

High impact information on HAP1

• All three of these proteins contain a short sequence, the heme regulatory motif (HRM), that occurs six times adjacent to the HAP1 DNA binding domain, twice in the leader targeting sequence of ALAS and twice near the catalytic domain of the HRI kinase [8].
• Huntingtin-associated protein 1 regulates inhibitory synaptic transmission by modulating gamma-aminobutyric acid type A receptor membrane trafficking [9].
• Furthermore, SBMA-mutant-ARQ65-induced apoptosis was suppressed by cotransfection with HAP1 [10].
• Identification of residues in the human DNA repair enzyme HAP1 (Ref-1) that are essential for redox regulation of Jun DNA binding [3].
• By site-directed mutagenesis, cysteine 65 was identified as the redox active site in the HAP1 enzyme [3].

Chemical compound and disease context of HAP1

• HAP1 [methyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate], a heteroaryldihydropyrimidine, is a potent HBV capsid assembly activator and misdirector [5].

Biological context of HAP1

• HAP1 (Human AP endonuclease 1), the major enzyme in human cells initiating repair of AP sites, shows strong sequence homology to DNA repair enzymes from bacteria, Drosophila and other mammalian species [11].
• Ten promoter polymorphisms (9 previously unreported) displayed strong linkage disequilibrium, yielding identification of three frequently observed haplotypes [HAP1 (43%), HAP2 (36%), and HAP3 (8%)] [12].
• However, other rare or common apoE phenotypes have been observed in patients with type III HLP [13].
• Identification of a putative active site cysteine residue should facilitate analysis of the mechanism by which the HAP1 protein may alter the redox state of a wide range of transcription factors [3].
• It is concluded that the HAP1 protein has evolved a novel redox activation domain capable of regulating the DNA binding activity of a proto-oncogene product which is not essential for its DNA repair functions [3].

Anatomical context of HAP1

• Our study also demonstrates that mitochondrial genetic status plays a key role in regulation of a multifunctional protein APE1 (also known as Ref1 or HAP1) involved in transcription and DNA repair in the nucleus and the mitochondria [14].
• Jun protein inactivated by oxidation of this residue can be efficiently reactivated by a factor from human cell nuclei, recently identified as a DNA repair enzyme (termed HAP1 or Ref-1) [3].
• Stable HeLa cell transfectants expressing HAP1 antisense RNA were found to express greatly reduced levels of the HAP1 protein compared to equivalent sense orientation and vector-only control transfectants [4].
• No tissue localisation of HAP1-like immunoreactivity was observed in normal ovarian surface epithelium [15].
• Immunohistochemical localisation of HAP1-like activity was present in malignant ovarian epithelium and stroma but strong immunostaining was present in blood vessels, areas with myxomatous stroma and vascular spaces [15].

Associations of HAP1 with chemical compounds

• Basal HAP3 reporter activity was significantly elevated (1.8-fold) but decreased to the same levels as HAP2 and HAP1 with increasing concentrations of sulforaphane, benzyl isothiocyanate (BITC), and epigallocatechin gallate (EGCG) [12].
• The antisense HAP1 transfectants exhibited a normal growth rate, cell morphology and plating efficiency, but were hypersensitive to killing by a wide range of DNA damaging agents, including methyl methanesulphonate, hydrogen peroxide, menadione, and paraquat [4].
• The ability of lucanthone to inhibit the normal repair of abasic sites might reflect inhibition of apurinic/apyrimidinic endonuclease (HAP1) by the drug, thereby preventing an early step in the base excision repair pathway [16].
• Surprisingly, the NF-kappa B and HLP-1 binding activities were substantially inhibited in acyclovir-treated cells [17].
• Of the male subjects with HLP 1/3-1/2 had a diabetic or borderline i.v. glucose tolerance [18].

Other interactions of HAP1

• Further identification of the spots at different pathological grades was confirmed by Western blotting using monoclonal antibody against a haptoglobin epitope contained within HAP1 [15].
• Activation of the HIV-1 provirus correlated with the activation of binding of 55- and 85-kDa proteins to the kappa B enhancer and binding of the 50-kDa HLP-1 protein to the LBP-1 sequences of the HIV-1 long terminal repeat [17].

Analytical, diagnostic and therapeutic context of HAP1

• These data highlight the need to assess circulating concentration of HAP1 in the serum of ovarian cancer patients and evaluate its potential as a biomarker in the early diagnosis of ovarian cancer [15].

References