DNA polymerase beta

DNA polymerase beta, also known as POLB, is an enzyme present in eukaryotes. In humans, it is encoded by the POLB gene.[5]

POLB
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1BPX, 1BPY, 1BPZ, 1MQ2, 1MQ3, 1TV9, 1TVA, 1ZJM, 1ZJN, 1ZQA, 1ZQB, 1ZQC, 1ZQD, 1ZQE, 1ZQF, 1ZQG, 1ZQH, 1ZQI, 1ZQJ, 1ZQK, 1ZQL, 1ZQM, 1ZQN, 1ZQO, 1ZQP, 1ZQQ, 1ZQR, 1ZQS, 1ZQT, 2FMP, 2FMQ, 2FMS, 2I9G, 2ISO, 2ISP, 2P66, 2PXI, 3C2K, 3C2L, 3C2M, 3GDX, 3ISB, 3ISC, 3ISD, 3JPN, 3JPO, 3JPP, 3JPQ, 3JPR, 3JPS, 3JPT, 3LK9, 3MBY, 3OGU, 3RH4, 3RH5, 3RH6, 3RJE, 3RJF, 3RJG, 3RJH, 3RJI, 3RJJ, 3RJK, 3TFR, 3TFS, 4DO9, 4DOA, 4DOB, 4DOC, 4F5N, 4F5O, 4F5P, 4F5Q, 4F5R, 4GXI, 4GXJ, 4GXK, 4JWM, 4JWN, 4KLD, 4KLE, 4KLF, 4KLG, 4KLH, 4KLI, 4KLJ, 4KLL, 4KLM, 4KLO, 4KLQ, 4KLS, 4KLT, 4KLU, 4LVS, 4M2Y, 4M47, 4M9G, 4M9H, 4M9J, 4M9L, 4M9N, 4MF2, 4MF8, 4MFA, 4MFC, 4MFF, 4NLK, 4NLN, 4NLZ, 4NM1, 4NM2, 4NXZ, 4NY8, 4O5C, 4O5E, 4O5K, 4O9M, 4P2H, 4PGQ, 4PGX, 4PGY, 4PH5, 4PHA, 4PHD, 4PHE, 4PHP, 4PPX, 4R63, 4R64, 4R65, 4R66, 4RPX, 4RPY, 4RPZ, 4RQ0, 4RQ1, 4RQ2, 4RQ3, 4RQ4, 4RQ5, 4RQ6, 4RQ7, 4RQ8, 4RT2, 4RT3, 4TUP, 4TUQ, 4TUR, 4TUS, 4UAW, 4UAY, 4UAZ, 4UB1, 4UB2, 4UB3, 4UB4, 4UB5, 4UBB, 4UBC, 7ICE, 7ICF, 7ICG, 7ICH, 7ICI, 7ICJ, 7ICK, 7ICL, 7ICM, 7ICN, 7ICO, 7ICP, 7ICQ, 7ICR, 7ICS, 7ICT, 7ICU, 7ICV, 8ICA, 8ICB, 8ICC, 8ICE, 8ICF, 8ICG, 8ICH, 8ICI, 8ICJ, 8ICK, 8ICL, 8ICM, 8ICN, 8ICO, 8ICP, 8ICQ, 8ICR, 8ICS, 8ICT, 8ICU, 8ICV, 8ICW, 8ICX, 8ICY, 8ICZ, 9ICA, 9ICB, 9ICC, 9ICE, 9ICF, 9ICG, 9ICH, 9ICI, 9ICJ, 9ICK, 9ICL, 9ICM, 9ICN, 9ICO, 9ICP, 9ICQ, 9ICR, 9ICS, 9ICT, 9ICU, 9ICV, 9ICW, 9ICX, 9ICY, 5BOL, 5BOM, 5BPC, 5DB8, 5DBB, 5DBA, 5DB7, 5DBC, 5DB9, 5DB6, 4YMN, 4YN4, 4YMO, 4YMM, 4Z6C, 4Z6F, 4Z6D, 4Z6E
Identifiers
Aliases	POLB, DNA polymerase beta
External IDs	OMIM: 174760 MGI: 97740 HomoloGene: 2013 GeneCards: POLB
Gene location (Human) Chr. Chromosome 8 (human)[1] Band 8p11.21 Start 42,338,454 bp[1] End 42,371,808 bp[1]
Gene location (Mouse) Chr. Chromosome 8 (mouse)[2] Band 8 A2|8 11.42 cM Start 22,628,126 bp[2] End 22,653,435 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • transferase activity • DNA binding • nucleotidyltransferase activity • microtubule binding • metal ion binding • damaged DNA binding • GO:0001948 protein binding • lyase activity • enzyme binding • DNA-directed DNA polymerase activity • DNA-(apurinic or apyrimidinic site) lyase activity • DNA polymerase • DNA polymerase activity Cellular component • cytoplasm • nucleoplasm • spindle microtubule • microtubule • cell nucleus • macromolecular complex Biological process • neuron apoptotic process • somatic hypermutation of immunoglobulin genes • pyrimidine dimer repair • nucleotide-excision repair, DNA gap filling • DNA-dependent DNA replication • DNA biosynthetic process • homeostasis of number of cells • response to hyperoxia • aging • spleen development • salivary gland morphogenesis • cellular response to DNA damage stimulus • immunoglobulin heavy chain V-D-J recombination • DNA replication • somatic diversification of immunoglobulins • base-excision repair, gap-filling • intrinsic apoptotic signaling pathway in response to DNA damage • response to ethanol • inflammatory response • lymph node development • response to gamma radiation • DNA repair • apoptotic process • base-excision repair • base-excision repair, DNA ligation • base-excision repair, base-free sugar-phosphate removal • protein deubiquitination • double-strand break repair via nonhomologous end joining Sources:Amigo / QuickGO
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	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Stem loopII regulatory element in POLB
Predicted secondary structure of the stem loopII (M2) regulatory element in POLB
Identifiers
Symbol	POLB
Rfam	RF01455
NCBI Gene	5423
HGNC	9174
OMIM	174760
RefSeq	NM_002690
Other data
RNA type	Cis-reg
Domain(s)	Mammalia
Locus	Chr. 8 p11.2
PDB structures	PDBe

Function

In eukaryotic cells, DNA polymerase beta (POLB) performs base excision repair (BER) required for DNA maintenance, replication, recombination, and drug resistance.[5]

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.[6] POLB thus has a key role in maintaining the stability of the mitochondrial genome.[6]

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.[7] This finding was considered to provide evidence against the error catastrophe theory of aging.[7][8]

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. Therefore, it is essential that POLB expression is tightly regulated.[9][10][11][12]

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.[13][14] 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.[15] 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[16] and XRCC1.[17][18][19][20]

See also

• POLA1
• POLA2

Model organisms

Model organisms have been used in the study of POLB function. A conditional knockout mouse line called Polb^{tm1a(KOMP)Wtsi} was generated at the Wellcome Trust Sanger Institute.[21] Male and female animals underwent a standardized phenotypic screen[22] to determine the effects of deletion.[23][24][25][26] Additional screens performed: - In-depth immunological phenotyping[27]

Polb knockout mouse phenotype

Characteristic	Phenotype
All data available at.[22][27]{
Peripheral blood leukocytes 6 Weeks	Normal
Haematology 6 Weeks	Normal
Homozygous viability at P14	Abnormal
Recessive lethal study	Abnormal
Body weight	Normal
Neurological assessment	Normal
Grip strength	Normal
Dysmorphology	Normal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Normal
Eye morphology	Normal
Clinical chemistry	Normal
Haematology 16 Weeks	Normal
Peripheral blood leukocytes 16 Weeks	Normal
Heart weight	Normal
Salmonella infection	Normal
Cytotoxic T Cell Function	Normal
Spleen Immunophenotyping	Normal
Mesenteric Lymph Node Immunophenotyping	Normal
Bone Marrow Immunophenotyping	Normal
Epidermal Immune Composition	Normal
Trichuris Challenge	Normal

References

1. GRCh38: Ensembl release 89: ENSG00000070501 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000031536 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "NCBI Gene: DNA polymerase beta".
6. 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 (December 2017). "DNA polymerase β: A missing link of the base excision repair machinery in mammalian mitochondria". DNA Repair (Amst.). 60: 77–88. doi:10.1016/j.dnarep.2017.10.011. PMC 5919216. PMID 29100041.
7. Subba Rao K, Martin GM, Loeb LA (October 1985). "Fidelity of DNA polymerase-beta in neurons from young and very aged mice". J. Neurochem. 45 (4): 1273–8. doi:10.1111/j.1471-4159.1985.tb05553.x. PMID 3161998.
8. Orgel LE (June 1973). "Ageing of clones of mammalian cells". Nature. 243 (5408): 441–5. doi:10.1038/243441a0. PMID 4591306.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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. doi:10.1002/j.1460-2075.1996.tb01056.x. PMC 452490. PMID 8978692.
20. 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.
21. 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.
22. "International Mouse Phenotyping Consortium".
23. 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.
24. Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
25. 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.
26. 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.
27. "Infection and Immunity Immunophenotyping (3i) Consortium".

Further reading

• Date T, Tanihara K, Yamamoto S, Nomura N, Matsukage A (Sep 1992). "Two regions in human DNA polymerase beta mRNA suppress translation in Escherichia coli". Nucleic Acids Research. 20 (18): 4859–64. doi:10.1093/nar/20.18.4859. PMC 334243. PMID 1408801.
• Wang L, Patel U, Ghosh L, Banerjee S (Sep 1992). "DNA polymerase beta mutations in human colorectal cancer". Cancer Research. 52 (17): 4824–7. PMID 1511447.
• Tokui T, Inagaki M, Nishizawa K, Yatani R, Kusagawa M, Ajiro K, Nishimoto Y, Date T, Matsukage A (Jun 1991). "Inactivation of DNA polymerase beta by in vitro phosphorylation with protein kinase C". The Journal of Biological Chemistry. 266 (17): 10820–4. PMID 2040602.
• SenGupta DN, Zmudzka BZ, Kumar P, Cobianchi F, Skowronski J, Wilson SH (Apr 1986). "Sequence of human DNA polymerase beta mRNA obtained through cDNA cloning". Biochemical and Biophysical Research Communications. 136 (1): 341–7. doi:10.1016/0006-291X(86)90916-2. PMID 2423078.
• Zmudzka BZ, Fornace A, Collins J, Wilson SH (Oct 1988). "Characterization of DNA polymerase beta mRNA: cell-cycle and growth response in cultured human cells". Nucleic Acids Research. 16 (20): 9587–96. doi:10.1093/nar/16.20.9587. PMC 338765. PMID 2460824.
• Widen SG, Kedar P, Wilson SH (Nov 1988). "Human beta-polymerase gene. Structure of the 5'-flanking region and active promoter". The Journal of Biological Chemistry. 263 (32): 16992–8. PMID 3182828.
• Abbotts J, SenGupta DN, Zmudzka B, Widen SG, Notario V, Wilson SH (Feb 1988). "Expression of human DNA polymerase beta in Escherichia coli and characterization of the recombinant enzyme". Biochemistry. 27 (3): 901–9. doi:10.1021/bi00403a010. PMID 3284575.
• Dobashi Y, Kubota Y, Shuin T, Torigoe S, Yao M, Hosaka M (Apr 1995). "Polymorphisms in the human DNA polymerase beta gene". Human Genetics. 95 (4): 389–90. doi:10.1007/bf00208961. PMID 7705833.
• Chyan YJ, Ackerman S, Shepherd NS, McBride OW, Widen SG, Wilson SH, Wood TG (Jul 1994). "The human DNA polymerase beta gene structure. Evidence of alternative splicing in gene expression". Nucleic Acids Research. 22 (14): 2719–25. doi:10.1093/nar/22.14.2719. PMC 308239. PMID 7914364.
• Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Chang M, Burmer GC, Sweasy J, Loeb LA, Edelhoff S, Disteche CM, Yu CE, Anderson L, Oshima J, Nakura J (May 1994). "Evidence against DNA polymerase beta as a candidate gene for Werner syndrome". Human Genetics. 93 (5): 507–12. doi:10.1007/bf00202813. PMID 8168825.
• Chyan YJ, Strauss PR, Wood TG, Wilson SH (Aug 1996). "Identification of novel mRNA isoforms for human DNA polymerase beta". DNA and Cell Biology. 15 (8): 653–9. doi:10.1089/dna.1996.15.653. PMID 8769567.
• Pelletier H, Sawaya MR, Wolfle W, Wilson SH, Kraut J (Oct 1996). "Crystal structures of human DNA polymerase beta complexed with DNA: implications for catalytic mechanism, processivity, and fidelity". Biochemistry. 35 (39): 12742–61. doi:10.1021/bi952955d. PMID 8841118.
• Pelletier H, Sawaya MR, Wolfle W, Wilson SH, Kraut J (Oct 1996). "A structural basis for metal ion mutagenicity and nucleotide selectivity in human DNA polymerase beta". Biochemistry. 35 (39): 12762–77. doi:10.1021/bi9529566. PMID 8841119.
• Pelletier H, Sawaya MR (Oct 1996). "Characterization of the metal ion binding helix-hairpin-helix motifs in human DNA polymerase beta by X-ray structural analysis". Biochemistry. 35 (39): 12778–87. doi:10.1021/bi960790i. PMID 8841120.
• 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. doi:10.1002/j.1460-2075.1996.tb01056.x. PMC 452490. PMID 8978692.
• Bennett RA, Wilson DM, Wong D, Demple B (Jul 1997). "Interaction of human apurinic endonuclease and DNA polymerase beta in the base excision repair pathway". Proceedings of the National Academy of Sciences of the United States of America. 94 (14): 7166–9. doi:10.1073/pnas.94.14.7166. PMC 23779. PMID 9207062.
• Sawaya MR, Prasad R, Wilson SH, Kraut J, Pelletier H (Sep 1997). "Crystal structures of human DNA polymerase beta complexed with gapped and nicked DNA: evidence for an induced fit mechanism". Biochemistry. 36 (37): 11205–15. doi:10.1021/bi9703812. PMID 9287163.
• Bhattacharyya N, Banerjee S (Sep 1997). "A variant of DNA polymerase beta acts as a dominant negative mutant". Proceedings of the National Academy of Sciences of the United States of America. 94 (19): 10324–9. doi:10.1073/pnas.94.19.10324. PMC 23361. PMID 9294209.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Tan XH, Zhao M, Pan KF, Dong Y, Dong B, Feng GJ, Jia G, Lu YY (Mar 2005). "Frequent mutation related with overexpression of DNA polymerase beta in primary tumors and precancerous lesions of human stomach". Cancer Letters. 220 (1): 101–14. doi:10.1016/j.canlet.2004.07.049. PMID 15737693.

External links

• Rfam entry for the stem loopII (M2) regulatory element in POLB