Disease relevance of Polb

• Pol-beta-deficient cells were significantly more susceptible to killing by temozolomide than wild-type or Aag-deficient cells, a hypersensitivity likely caused by accumulation of BER intermediates [1].
• On the other hand, Pol beta-deficient cells proved to be highly sensitive to methylation-induced chromosomal aberrations and reproductive cell death [2].
• Cells deficient in DNA polymerase beta are hypersensitive to alkylating agent-induced apoptosis and chromosomal breakage [3].
• Unique requirements for template primers of DNA polymerase beta from rat ascites hepatoma AH130 cells [4].
• Activation of the mouse DNA polymerase beta gene promoter by adenovirus type 12 E1A proteins [5].

High impact information on Polb

• Requirement of mammalian DNA polymerase-beta in base-excision repair [6].
• Because genetic studies are essential for determining the physiological role of a gene, we established embryonic fibroblast cell lines homozygous for a deletion mutation in the gene encoding DNA polymerase-beta [6].
• Deletion of the promoter and the first exon of the DNA polymerase beta gene (pol beta) in the mouse germ line results in a lethal phenotype [7].
• Deletion of a DNA polymerase beta gene segment in T cells using cell type-specific gene targeting [7].
• The inability of TdT to accommodate a template strand can be explained by steric hindrance at the catalytic site caused by a long lariat-like loop, which is absent in DNA polymerase beta [8].

Chemical compound and disease context of Polb

• Using a complementation system, in which rat DNA polymerase beta substitutes for DNA polymerase I of Escherichia coli, we previously isolated a DNA polymerase beta mutant in which Tyr-265 was altered to Cys (Y265C) [9].
• In this study, we show that treatment with the 2',3'-dideoxycytidine (ddC) nucleoside analog inhibited in vitro and in vivo the proliferation of Pol beta-transfected B16 melanoma cells, which up-regulate Pol beta compared with control isogenic cells [10].
• A protein factor having exonucleolytic activity on bleomycin-damaged DNA and providing priming sites for DNA polymerases existed in a DNA polymerase beta fraction partially purified by ion exchange chromatography from an extract of permeable mouse ascites sarcoma (SR-C3H/He) cells [11].
• Our previous studies exploring melphalan resistance in the human rhabdomyosarcoma xenograft TE-671 MR revealed elevation of DNA polymerase-alpha and DNA polymerase-beta [12].
• 4. Peplomycin-induced, single-strand breaks in pUC18 DNA was repaired by incubating with a priming factor (an exonuclease purified from mouse ascites sarcoma cells), DNA polymerase beta, four deoxynucleoside triphosphates, T4 DNA ligase and ATP [13].

Biological context of Polb

• DNA polymerase beta (Polbeta) has been implicated in base excision repair [14].
• Genetic interaction between DNA polymerase beta and DNA-PKcs in embryogenesis and neurogenesis [14].
• Decreased PARP-1 levels accelerate embryonic lethality but attenuate neuronal apoptosis in DNA polymerase beta-deficient mice [15].
• Three major transcription initiation sites (cap sites) each for rat and mouse DNA polymerase beta mRNAs were localized precisely by primer extension analysis at 51, 41, and 0 bp upstream from the first ATG codon, suggesting that this codon is used for translation initiation [16].
• Murine DNA polymerase beta gene: mapping of transcription initiation sites and the nucleotide sequence of the putative promoter region [16].

Anatomical context of Polb

• For this purpose, we used mouse embryo fibroblasts derived from wild-type and Polb gene knockout littermates [17].
• Mice reconstituted with DNA polymerase beta-deficient fetal liver cells are able to mount a T cell-dependent immune response and mutate their Ig genes normally [18].
• Both wild-type and, in particular, repair-deficient DNA polymerase beta null cells are highly sensitized to the cytotoxic effects of MMS by 4-amino-1,8-naphthalimide (4-AN), an inhibitor of poly(ADP-ribose) polymerase (PARP) activity [19].
• Murine Pol lambda, consisting of 573 amino acid residues, has a 32% identity to Pol beta, involved in nuclear DNA repair in eukaryotic cells [20].
• The effect of the DNA polymerase-beta (beta-pol) deficiency on mitogenic response and cytokine production was studied in spleen lymphocytes from 4-5- and 20-22-month-old beta-pol(-/+) mice and their age-matched wild-type littermates [21].

Associations of Polb with chemical compounds

• In repair of the N-alkylated purine base lesion, for example, alkyl adenine DNA glycosylase (Aag) recognizes and removes the base, and DNA polymerase beta (beta-pol) contributes the gap tailoring and DNA synthesis steps [22].
• DNA polymerase beta (Pol beta) transfection was ineffective in conferring resistance to methylmethane sulfonate (MMS) [2].
• Mouse fibroblasts, deficient in DNA polymerase beta, are hypersensitive to monofunctional DNA methylating agents such as methyl methanesulfonate (MMS) [19].
• However, no up-regulation in either BER or its rate-determining enzyme, DNA polymerase beta (beta-pol) is observed in response to folate deficiency [23].
• Pol lambda also conserves the critical residues of Pol beta required for its intrinsic deoxyribose phosphate lyase (dRPase) activity [20].

Physical interactions of Polb

• We provided evidence that PARP-1 constitutively interacts with DNA polymerase beta [24].

Enzymatic interactions of Polb

• We have used cell extracts from Pol beta-deleted mouse fibroblasts to separate subfractions containing either Pol delta or Pol epsilon [25].

Regulatory relationships of Polb

• We found that REV1 expression is required for the MMS-induced mutagenesis phenotype of Pol beta null MEF cells [26].
• Mutator phenotype of BCR--ABL transfected Ba/F3 cell lines and its association with enhanced expression of DNA polymerase beta [27].

Other interactions of Polb

• In mammalian cells, DNA polymerase beta (Polbeta) and poly(ADP-ribose) polymerase-1 (PARP-1) have been implicated in base excision repair (BER) and single-strand break repair [15].
• Differential effect of p53 on the promoters of mouse DNA polymerase beta gene and proliferating-cell-nuclear-antigen gene [28].
• By analysis with various deletion mutants in the DNA polymerase beta gene promoter, we identified the unique 10-bp palindromic sequence (-24 to -15), in the presence of which p53 was not able to repress the promoter activity [28].
• We present evidence that short-patch repair synthesis occurs even in the absence of both Pol beta and replicative Pols [29].
• Cl-F-ara-ATP was not a potent inhibitor of DNA polymerase beta, DNA polymerase gamma, or DNA primase.(ABSTRACT TRUNCATED AT 400 WORDS)[30]

Analytical, diagnostic and therapeutic context of Polb

• Formation of palindromic (P) region at the variable (V)-diversity (D)-joining (J) junction in DNA polymerase beta (pol-beta) deficient mice were investigated by sequencing of reverse transcriptase-polymerase chain reaction (RT-PCR) products of mRNAs encoding the beta chain of T cell receptor (TCR) [31].
• We conducted Southern blot analysis of DNAs from mouse x hamster somatic cell hybrids and progeny of an interspecies backcross to localize the mouse gene for DNA polymerase beta (Polb) to the centromeric end of Chromosome 8 [32].
• The damage to gamma-actin and DNA polymerase-beta genes was detected within 20 min of reperfusion based on the presence of formamidopyrimidine DNA N-glycosylase-sensitive sites [33].
• Northern blot hybridization analysis using rat cDNA as a probe revealed that the mRNA of about 1.5 kb for this enzyme is present in all kinds of tissues examined, but its content widely varies among tissues; the most abundant DNA polymerase beta mRNA was present in the testis, which was followed by brain, thymus, and spleen [34].
• Using gel filtration of whole cell extracts prepared at physiological salt conditions (0.15 M NaCl), we find no evidence for a stable preexisting complex of DNA Pol beta with the DNA ligase IIIalpha-XRCC1 heterodimer [35].

References