DNA polymerase beta

Polymerase (DNA directed), beta

PDB rendering based on 1bno.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols POLB ; MGC125976
External IDs OMIM: 174760 MGI: 97740 HomoloGene: 2013 ChEMBL: 2392 GeneCards: POLB Gene
EC number 2.7.7.7
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 5423 18970
Ensembl ENSG00000070501 ENSMUSG00000031536
UniProt P06746 Q8K409
RefSeq (mRNA) NM_002690 NM_011130
RefSeq (protein) NP_002681 NP_035260
Location (UCSC) Chr 8:
42.34 – 42.37 Mb		 Chr 8:
22.63 – 22.65 Mb
PubMed search
Stem loopII regulatory element in POLB
Predicted secondary structure of the stem loopII (M2) regulatory element in POLB
Identifiers
Symbol POLB
Rfam RF01455
Entrez 5423
HUGO POLB
OMIM 174760
RefSeq NM_002690
Other data
RNA type Cis-reg
Domain(s) Mammalia
Locus Chr. 8 p11.2

Polymerase (DNA directed), beta, also known as POLB, is an enzyme that, in humans, 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]

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.[2][3][4][5]

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.[6][7] 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.[8] 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[9] and XRCC1.[10][11][12][13]

See also

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.[14] Male and female animals underwent a standardized phenotypic screen[15] to determine the effects of deletion.[16][17][18][19] Additional screens performed: - In-depth immunological phenotyping[20]

References

  1. 1 2 "Entrez Gene: POLB polymerase (DNA directed), beta".
  2. ↑ Canitrot Y, Cazaux C, Fréchet M, Bouayadi K, Lesca C, Salles B, Hoffmann JS (Oct 1998). "Overexpression of DNA polymerase beta in cell results in a mutator phenotype and a decreased sensitivity to anticancer drugs". Proceedings of the National Academy of Sciences of the United States of America 95 (21): 12586–90. doi:10.1073/pnas.95.21.12586. PMC 22874. PMID 9770529.
  3. ↑ 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 (Jun 2002). "Deregulated DNA polymerase beta induces chromosome instability and tumorigenesis". Cancer Research 62 (12): 3511–4. PMID 12067997.
  4. ↑ Bergoglio V, Canitrot Y, Hogarth L, Minto L, Howell SB, Cazaux C, Hoffmann JS (Sep 2001). "Enhanced expression and activity of DNA polymerase beta in human ovarian tumor cells: impact on sensitivity towards antitumor agents". Oncogene 20 (43): 6181–7. doi:10.1038/sj.onc.1204743. PMID 11593426.
  5. ↑ Srivastava DK, Husain I, Arteaga CL, Wilson SH (Jun 1999). "DNA polymerase beta expression differences in selected human tumors and cell lines". Carcinogenesis 20 (6): 1049–54. doi:10.1093/carcin/20.6.1049. PMID 10357787.
  6. ↑ He F, Yang XP, Srivastava DK, Wilson SH (Jan 2003). "DNA polymerase beta gene expression: the promoter activator CREB-1 is upregulated in Chinese hamster ovary cells by DNA alkylating agent-induced stress". Biological Chemistry 384 (1): 19–23. doi:10.1515/BC.2003.003. PMID 12674496.
  7. ↑ Narayan S, He F, Wilson SH (Aug 1996). "Activation of the human DNA polymerase beta promoter by a DNA-alkylating agent through induced phosphorylation of cAMP response element-binding protein-1". The Journal of Biological Chemistry 271 (31): 18508–13. doi:10.1074/jbc.271.31.18508. PMID 8702497.
  8. ↑ Sarnowska E, Grzybowska EA, Sobczak K, Konopinski R, Wilczynska A, Szwarc M, Sarnowski TJ, Krzyzosiak WJ, Siedlecki JA (2007). "Hairpin structure within the 3'UTR of DNA polymerase beta mRNA acts as a post-transcriptional regulatory element and interacts with Hax-1". Nucleic Acids Research 35 (16): 5499–510. doi:10.1093/nar/gkm502. PMC 2018635. PMID 17704138.
  9. ↑ Whitehouse CJ, Taylor RM, Thistlethwaite A, Zhang H, Karimi-Busheri F, Lasko DD, Weinfeld M, Caldecott KW (Jan 2001). "XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair". Cell 104 (1): 107–17. doi:10.1016/S0092-8674(01)00195-7. PMID 11163244.
  10. ↑ Wang L, Bhattacharyya N, Chelsea DM, Escobar PF, Banerjee S (Nov 2004). "A novel nuclear protein, MGC5306 interacts with DNA polymerase beta and has a potential role in cellular phenotype". Cancer Research 64 (21): 7673–7. doi:10.1158/0008-5472.CAN-04-2801. PMID 15520167.
  11. ↑ Fan J, Otterlei M, Wong HK, Tomkinson AE, Wilson DM (2004). "XRCC1 co-localizes and physically interacts with PCNA". Nucleic Acids Research 32 (7): 2193–201. doi:10.1093/nar/gkh556. PMC 407833. PMID 15107487.
  12. ↑ Kubota Y, Nash RA, Klungland A, Schär P, Barnes DE, Lindahl T (Dec 1996). "Reconstitution of DNA base excision-repair with purified human proteins: interaction between DNA polymerase beta and the XRCC1 protein". The EMBO Journal 15 (23): 6662–70. PMC 452490. PMID 8978692.
  13. ↑ Bhattacharyya N, Banerjee S (Jul 2001). "A novel role of XRCC1 in the functions of a DNA polymerase beta variant". Biochemistry 40 (30): 9005–13. doi:10.1021/bi0028789. PMID 11467963.
  14. ↑ Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Ophthalmologica 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
  15. 1 2 "International Mouse Phenotyping Consortium".
  16. ↑ 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 (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
  17. ↑ Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
  18. ↑ Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
  19. ↑ 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 (Jul 2013). "Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes". Cell 154 (2): 452–64. doi:10.1016/j.cell.2013.06.022. PMC 3717207. PMID 23870131.
  20. 1 2 "Infection and Immunity Immunophenotyping (3i) Consortium".

Further reading

External links

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