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词条 DNA polymerase beta
释义

  1. Function

  2. Regulation of expression

  3. Interactions

  4. See also

  5. Model organisms

  6. References

  7. Further reading

  8. External links

{{Infobox_gene}}{{Infobox rfam
| Name = Stem loopII regulatory element in POLB
| image = RF01455.png
| width = 200
| caption = Predicted secondary structure of the stem loopII (M2) regulatory element in POLB
| Symbol = POLB
| AltSymbols =
| Rfam = RF01455
| miRBase =
| miRBase_family =
| RNA_type = Cis-reg
| Tax_domain = Mammalia
| CAS_number =
| EntrezGene = 5423
| HGNCid = POLB
| OMIM = 174760
| PDB =
| RefSeq = NM_002690
| Chromosome = 8
| Arm = p
| Band = 11.2
| LocusSupplementaryData =
}}DNA polymerase, beta, also known as POLB, is an enzyme present in eukaryotes. In humans, it is encoded by the POLB gene.[1]

Function

In eukaryotic cells, DNA polymerase beta (POLB) performs base excision repair (BER) required for DNA maintenance, replication, recombination, and drug resistance.[1]

The mitochondrial DNA of mammalian cells is constantly under attack from oxygen radicals released during ATP production. Mammalian cell mitochondria contain an efficient base excision repair system employing POLB that removes some frequent oxidative DNA damages.[2] POLB thus has a key role in maintaining the stability of the mitochondrial genome.[2]

An analysis of the fidelity of DNA replication by polymerase beta in the neurons from young and very aged mice indicated that aging has no significant effect on the fidelity of DNA synthesis by polymerase beta.[3] This finding was considered to provide evidence against the error catastrophe theory of aging.[3][4]

Regulation of expression

DNA polymerase beta maintains genome integrity by participating in base excision repair. Overexpression of POLB mRNA has been correlated with a number of cancer types, whereas deficiencies in POLB results in hypersensitivity to alkylating agents, induced apoptosis, and chromosomal breaking [ref7]. Therefore, it is essential that POLB expression is tightly regulated.[5][6][7][8]

POLB gene is upregulated by CREB1 transcription factor's binding to the cAMP response element(CRE) present in the promoter of the POLB gene in response to exposure to alkylating agents.[9][10] POLB gene expression is also regulated at the post transcriptional level as the 3’UTR of the POLB mRNA has been shown to contain three stem-loop structures that influence gene expression.[11] These three-stem loop structures are known as M1, M2, and M3, where M2 and M3 have a key role in gene regulation. M3 contributes to gene expression, as it contains the polyadenylation signal followed by the cleavage and polyadenylation site, thereby contributing to pre-mRNA processing. M2 has been shown to be evolutionary conserved, and, through mutagenesis, it was shown that this stem loop structure acts as a RNA destabilizing element.

In addition to these cis-regulatory elements present within the 3’UTR a trans-acting protein, HAX1 is thought to contribute to the regulation of gene expression. Yeast three-hybrid assays have shown that this protein binds to the stem loops within the 3’UTR of the POLB mRNA, however the exact mechanism in how this protein regulates gene expression is still to be determined.

Interactions

DNA polymerase beta has been shown to interact with PNKP[12] and XRCC1.[13][14][15][16]

See also

  • POLA1
  • POLA2

Model organisms

Model organisms have been used in the study of POLB function. A conditional knockout mouse line called Polbtm1a(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute.[17] Male and female animals underwent a standardized phenotypic screen[18] to determine the effects of deletion.[19][20][21][22] Additional screens performed: - In-depth immunological phenotyping[23]{{clear|left}}

References

1. ^1 {{cite web | title = Entrez Gene: POLB polymerase (DNA directed), beta| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5423| accessdate = }}
2. ^1 {{cite journal |vauthors=Prasad R, Çağlayan M, Dai DP, Nadalutti CA, Zhao ML, Gassman NR, Janoshazi AK, Stefanick DF, Horton JK, Krasich R, Longley MJ, Copeland WC, Griffith JD, Wilson SH |title=DNA polymerase β: A missing link of the base excision repair machinery in mammalian mitochondria |journal=DNA Repair (Amst.) |volume=60 |issue= |pages=77–88 |date=December 2017 |pmid=29100041 |doi=10.1016/j.dnarep.2017.10.011 |url=}}
3. ^1 {{cite journal |vauthors=Subba Rao K, Martin GM, Loeb LA |title=Fidelity of DNA polymerase-beta in neurons from young and very aged mice |journal=J. Neurochem. |volume=45 |issue=4 |pages=1273–8 |date=October 1985 |pmid=3161998 |doi= |url=}}
4. ^{{cite journal |vauthors=Orgel LE |title=Ageing of clones of mammalian cells |journal=Nature |volume=243 |issue=5408 |pages=441–5 |date=June 1973 |pmid=4591306 |doi= |url=}}
5. ^{{cite journal | vauthors = Canitrot Y, Cazaux C, Fréchet M, Bouayadi K, Lesca C, Salles B, Hoffmann JS | title = Overexpression of DNA polymerase beta in cell results in a mutator phenotype and a decreased sensitivity to anticancer drugs | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 21 | pages = 12586–90 | date = Oct 1998 | pmid = 9770529 | pmc = 22874 | doi = 10.1073/pnas.95.21.12586 }}
6. ^{{cite journal | vauthors = Bergoglio V, Pillaire MJ, Lacroix-Triki M, Raynaud-Messina B, Canitrot Y, Bieth A, Garès M, Wright M, Delsol G, Loeb LA, Cazaux C, Hoffmann JS | title = Deregulated DNA polymerase beta induces chromosome instability and tumorigenesis | journal = Cancer Research | volume = 62 | issue = 12 | pages = 3511–4 | date = Jun 2002 | pmid = 12067997 | doi = }}
7. ^{{cite journal | vauthors = Bergoglio V, Canitrot Y, Hogarth L, Minto L, Howell SB, Cazaux C, Hoffmann JS | title = Enhanced expression and activity of DNA polymerase beta in human ovarian tumor cells: impact on sensitivity towards antitumor agents | journal = Oncogene | volume = 20 | issue = 43 | pages = 6181–7 | date = Sep 2001 | pmid = 11593426 | doi = 10.1038/sj.onc.1204743 }}
8. ^{{cite journal | vauthors = Srivastava DK, Husain I, Arteaga CL, Wilson SH | title = DNA polymerase beta expression differences in selected human tumors and cell lines | journal = Carcinogenesis | volume = 20 | issue = 6 | pages = 1049–54 | date = Jun 1999 | pmid = 10357787 | doi = 10.1093/carcin/20.6.1049 }}
9. ^{{cite journal | vauthors = He F, Yang XP, Srivastava DK, Wilson SH | title = DNA polymerase beta gene expression: the promoter activator CREB-1 is upregulated in Chinese hamster ovary cells by DNA alkylating agent-induced stress | journal = Biological Chemistry | volume = 384 | issue = 1 | pages = 19–23 | date = Jan 2003 | pmid = 12674496 | doi = 10.1515/BC.2003.003 }}
10. ^{{cite journal | vauthors = Narayan S, He F, Wilson SH | title = Activation of the human DNA polymerase beta promoter by a DNA-alkylating agent through induced phosphorylation of cAMP response element-binding protein-1 | journal = The Journal of Biological Chemistry | volume = 271 | issue = 31 | pages = 18508–13 | date = Aug 1996 | pmid = 8702497 | doi = 10.1074/jbc.271.31.18508 }}
11. ^{{cite journal | vauthors = Sarnowska E, Grzybowska EA, Sobczak K, Konopinski R, Wilczynska A, Szwarc M, Sarnowski TJ, Krzyzosiak WJ, Siedlecki JA | title = Hairpin structure within the 3'UTR of DNA polymerase beta mRNA acts as a post-transcriptional regulatory element and interacts with Hax-1 | journal = Nucleic Acids Research | volume = 35 | issue = 16 | pages = 5499–510 | year = 2007 | pmid = 17704138 | pmc = 2018635 | doi = 10.1093/nar/gkm502 }}
12. ^{{cite journal | vauthors = Whitehouse CJ, Taylor RM, Thistlethwaite A, Zhang H, Karimi-Busheri F, Lasko DD, Weinfeld M, Caldecott KW | title = XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair | journal = Cell | volume = 104 | issue = 1 | pages = 107–17 | date = Jan 2001 | pmid = 11163244 | doi = 10.1016/S0092-8674(01)00195-7 }}
13. ^{{cite journal | vauthors = Wang L, Bhattacharyya N, Chelsea DM, Escobar PF, Banerjee S | title = A novel nuclear protein, MGC5306 interacts with DNA polymerase beta and has a potential role in cellular phenotype | journal = Cancer Research | volume = 64 | issue = 21 | pages = 7673–7 | date = Nov 2004 | pmid = 15520167 | doi = 10.1158/0008-5472.CAN-04-2801 }}
14. ^{{cite journal | vauthors = Fan J, Otterlei M, Wong HK, Tomkinson AE, Wilson DM | title = XRCC1 co-localizes and physically interacts with PCNA | journal = Nucleic Acids Research | volume = 32 | issue = 7 | pages = 2193–201 | year = 2004 | pmid = 15107487 | pmc = 407833 | doi = 10.1093/nar/gkh556 }}
15. ^{{cite journal | vauthors = Kubota Y, Nash RA, Klungland A, Schär P, Barnes DE, Lindahl T | title = Reconstitution of DNA base excision-repair with purified human proteins: interaction between DNA polymerase beta and the XRCC1 protein | journal = The EMBO Journal | volume = 15 | issue = 23 | pages = 6662–70 | date = Dec 1996 | pmid = 8978692 | pmc = 452490 }}
16. ^{{cite journal | vauthors = Bhattacharyya N, Banerjee S | title = A novel role of XRCC1 in the functions of a DNA polymerase beta variant | journal = Biochemistry | volume = 40 | issue = 30 | pages = 9005–13 | date = Jul 2001 | pmid = 11467963 | doi = 10.1021/bi0028789 }}
17. ^{{cite journal |title=The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice |author=Gerdin AK |year=2010 |journal=Acta Ophthalmologica|volume=88 |pages=925–7|doi=10.1111/j.1755-3768.2010.4142.x }}
18. ^1 {{cite web |url=http://www.mousephenotype.org/data/search?q=Polb#fq=**&facet=gene |title=International Mouse Phenotyping Consortium}}
19. ^{{cite journal | vauthors = Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A | title = A conditional knockout resource for the genome-wide study of mouse gene function | journal = Nature | volume = 474 | issue = 7351 | pages = 337–42 | date = Jun 2011 | pmid = 21677750 | pmc = 3572410 | doi = 10.1038/nature10163 }}
20. ^{{cite journal | vauthors = Dolgin E | title = Mouse library set to be knockout | journal = Nature | volume = 474 | issue = 7351 | pages = 262–3 | date = Jun 2011 | pmid = 21677718 | doi = 10.1038/474262a }}
21. ^{{cite journal | vauthors = Collins FS, Rossant J, Wurst W | title = A mouse for all reasons | journal = Cell | volume = 128 | issue = 1 | pages = 9–13 | date = Jan 2007 | pmid = 17218247 | doi = 10.1016/j.cell.2006.12.018 }}
22. ^{{cite journal | vauthors = White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC, Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A, Steel KP | title = Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes | journal = Cell | volume = 154 | issue = 2 | pages = 452–64 | date = Jul 2013 | pmid = 23870131 | pmc = 3717207 | doi = 10.1016/j.cell.2013.06.022 }}
23. ^1 {{cite web |url= http://www.immunophenotyping.org/data/search?keys=Polb&field_gene_construct_tid=All |title=Infection and Immunity Immunophenotyping (3i) Consortium}}

Further reading

{{refbegin |35em}}
  • {{cite journal | vauthors = Date T, Tanihara K, Yamamoto S, Nomura N, Matsukage A | title = Two regions in human DNA polymerase beta mRNA suppress translation in Escherichia coli | journal = Nucleic Acids Research | volume = 20 | issue = 18 | pages = 4859–64 | date = Sep 1992 | pmid = 1408801 | pmc = 334243 | doi = 10.1093/nar/20.18.4859 }}
  • {{cite journal | vauthors = Wang L, Patel U, Ghosh L, Banerjee S | title = DNA polymerase beta mutations in human colorectal cancer | journal = Cancer Research | volume = 52 | issue = 17 | pages = 4824–7 | date = Sep 1992 | pmid = 1511447 | doi = }}
  • {{cite journal | vauthors = Tokui T, Inagaki M, Nishizawa K, Yatani R, Kusagawa M, Ajiro K, Nishimoto Y, Date T, Matsukage A | title = Inactivation of DNA polymerase beta by in vitro phosphorylation with protein kinase C | journal = The Journal of Biological Chemistry | volume = 266 | issue = 17 | pages = 10820–4 | date = Jun 1991 | pmid = 2040602 | doi = }}
  • {{cite journal | vauthors = SenGupta DN, Zmudzka BZ, Kumar P, Cobianchi F, Skowronski J, Wilson SH | title = Sequence of human DNA polymerase beta mRNA obtained through cDNA cloning | journal = Biochemical and Biophysical Research Communications | volume = 136 | issue = 1 | pages = 341–7 | date = Apr 1986 | pmid = 2423078 | doi = 10.1016/0006-291X(86)90916-2 }}
  • {{cite journal | vauthors = Zmudzka BZ, Fornace A, Collins J, Wilson SH | title = Characterization of DNA polymerase beta mRNA: cell-cycle and growth response in cultured human cells | journal = Nucleic Acids Research | volume = 16 | issue = 20 | pages = 9587–96 | date = Oct 1988 | pmid = 2460824 | pmc = 338765 | doi = 10.1093/nar/16.20.9587 }}
  • {{cite journal | vauthors = Widen SG, Kedar P, Wilson SH | title = Human beta-polymerase gene. Structure of the 5'-flanking region and active promoter | journal = The Journal of Biological Chemistry | volume = 263 | issue = 32 | pages = 16992–8 | date = Nov 1988 | pmid = 3182828 | doi = }}
  • {{cite journal | vauthors = Abbotts J, SenGupta DN, Zmudzka B, Widen SG, Notario V, Wilson SH | title = Expression of human DNA polymerase beta in Escherichia coli and characterization of the recombinant enzyme | journal = Biochemistry | volume = 27 | issue = 3 | pages = 901–9 | date = Feb 1988 | pmid = 3284575 | doi = 10.1021/bi00403a010 }}
  • {{cite journal | vauthors = Dobashi Y, Kubota Y, Shuin T, Torigoe S, Yao M, Hosaka M | title = Polymorphisms in the human DNA polymerase beta gene | journal = Human Genetics | volume = 95 | issue = 4 | pages = 389–90 | date = Apr 1995 | pmid = 7705833 | doi = 10.1007/bf00208961 }}
  • {{cite journal | vauthors = Chyan YJ, Ackerman S, Shepherd NS, McBride OW, Widen SG, Wilson SH, Wood TG | title = The human DNA polymerase beta gene structure. Evidence of alternative splicing in gene expression | journal = Nucleic Acids Research | volume = 22 | issue = 14 | pages = 2719–25 | date = Jul 1994 | pmid = 7914364 | pmc = 308239 | doi = 10.1093/nar/22.14.2719 }}
  • {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1-2 | pages = 171–4 | date = Jan 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
  • {{cite journal | vauthors = Chang M, Burmer GC, Sweasy J, Loeb LA, Edelhoff S, Disteche CM, Yu CE, Anderson L, Oshima J, Nakura J | title = Evidence against DNA polymerase beta as a candidate gene for Werner syndrome | journal = Human Genetics | volume = 93 | issue = 5 | pages = 507–12 | date = May 1994 | pmid = 8168825 | doi = 10.1007/bf00202813 }}
  • {{cite journal | vauthors = Chyan YJ, Strauss PR, Wood TG, Wilson SH | title = Identification of novel mRNA isoforms for human DNA polymerase beta | journal = DNA and Cell Biology | volume = 15 | issue = 8 | pages = 653–9 | date = Aug 1996 | pmid = 8769567 | doi = 10.1089/dna.1996.15.653 }}
  • {{cite journal | vauthors = Pelletier H, Sawaya MR, Wolfle W, Wilson SH, Kraut J | title = Crystal structures of human DNA polymerase beta complexed with DNA: implications for catalytic mechanism, processivity, and fidelity | journal = Biochemistry | volume = 35 | issue = 39 | pages = 12742–61 | date = Oct 1996 | pmid = 8841118 | doi = 10.1021/bi952955d }}
  • {{cite journal | vauthors = Pelletier H, Sawaya MR, Wolfle W, Wilson SH, Kraut J | title = A structural basis for metal ion mutagenicity and nucleotide selectivity in human DNA polymerase beta | journal = Biochemistry | volume = 35 | issue = 39 | pages = 12762–77 | date = Oct 1996 | pmid = 8841119 | doi = 10.1021/bi9529566 }}
  • {{cite journal | vauthors = Pelletier H, Sawaya MR | title = Characterization of the metal ion binding helix-hairpin-helix motifs in human DNA polymerase beta by X-ray structural analysis | journal = Biochemistry | volume = 35 | issue = 39 | pages = 12778–87 | date = Oct 1996 | pmid = 8841120 | doi = 10.1021/bi960790i }}
  • {{cite journal | vauthors = Kubota Y, Nash RA, Klungland A, Schär P, Barnes DE, Lindahl T | title = Reconstitution of DNA base excision-repair with purified human proteins: interaction between DNA polymerase beta and the XRCC1 protein | journal = The EMBO Journal | volume = 15 | issue = 23 | pages = 6662–70 | date = Dec 1996 | pmid = 8978692 | pmc = 452490 | doi = }}
  • {{cite journal | vauthors = Bennett RA, Wilson DM, Wong D, Demple B | title = Interaction of human apurinic endonuclease and DNA polymerase beta in the base excision repair pathway | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 14 | pages = 7166–9 | date = Jul 1997 | pmid = 9207062 | pmc = 23779 | doi = 10.1073/pnas.94.14.7166 }}
  • {{cite journal | vauthors = Sawaya MR, Prasad R, Wilson SH, Kraut J, Pelletier H | title = Crystal structures of human DNA polymerase beta complexed with gapped and nicked DNA: evidence for an induced fit mechanism | journal = Biochemistry | volume = 36 | issue = 37 | pages = 11205–15 | date = Sep 1997 | pmid = 9287163 | doi = 10.1021/bi9703812 }}
  • {{cite journal | vauthors = Bhattacharyya N, Banerjee S | title = A variant of DNA polymerase beta acts as a dominant negative mutant | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 19 | pages = 10324–9 | date = Sep 1997 | pmid = 9294209 | pmc = 23361 | doi = 10.1073/pnas.94.19.10324 }}
  • {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1-2 | pages = 149–56 | date = Oct 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
  • {{cite journal | vauthors = Tan XH, Zhao M, Pan KF, Dong Y, Dong B, Feng GJ, Jia G, Lu YY | title = Frequent mutation related with overexpression of DNA polymerase beta in primary tumors and precancerous lesions of human stomach | journal = Cancer Letters | volume = 220 | issue = 1 | pages = 101–14 | date = Mar 2005 | pmid = 15737693 | pmc = | doi = 10.1016/j.canlet.2004.07.049 }}
{{refend}}

External links

  • Rfam entry for the stem loopII (M2) regulatory element in POLB
{{PDB Gallery|geneid=5423}}

2 : DNA repair|DNA-binding proteins
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