DNA polymerase beta explained

Stem loopII regulatory element in POLB
Width:	200
Symbol:	POLB
Rfam:	RF01455
Rna Type:	Cis-reg
Tax Domain:	Mammalia
Entrezgene:	5423
Hgncid:	9174
Omim:	174760
Refseq:	NM_002690
Chromosome:	8
Arm:	p
Band:	11.2

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.

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.

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.^[4]

Base excision repair

Cabelof et al. measured the ability to repair DNA damage by the BER pathway in tissues of young (4-month-old) and old (24-month-old) mice.^[5] In all tissues examined (brain, liver, spleen and testes) the ability to repair DNA damage declined significantly with age, and the reduction in repair capability correlated with decreased levels of DNA polymerase beta at both the protein and messenger RNA levels. Numerous investigators have reported an accumulation of DNA damage with age, especially in brain and liver.^[6] Cabelof et al.^[5] suggested that the inability of the BER pathway to repair damages over time may provide a mechanistic explanation for the frequent observations of DNA accumulation of damage with age.

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.^{[7] [8] [9] [10]}

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.^{[11] [12]} 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.^[13] 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^[14] and XRCC1.^{[15] [16] [17] [18]}

See also

• POLA1
• POLA2

Further reading

• Date T, Tanihara K, Yamamoto S, Nomura N, Matsukage A . Two regions in human DNA polymerase beta mRNA suppress translation in Escherichia coli . Nucleic Acids Research . 20 . 18 . 4859–64 . September 1992 . 1408801 . 334243 . 10.1093/nar/20.18.4859 .
• Wang L, Patel U, Ghosh L, Banerjee S . DNA polymerase beta mutations in human colorectal cancer . Cancer Research . 52 . 17 . 4824–7 . September 1992 . 1511447 .
• Tokui T, Inagaki M, Nishizawa K, Yatani R, Kusagawa M, Ajiro K, Nishimoto Y, Date T, Matsukage A . 6 . Inactivation of DNA polymerase beta by in vitro phosphorylation with protein kinase C . The Journal of Biological Chemistry . 266 . 17 . 10820–4 . June 1991 . 10.1016/S0021-9258(18)99092-7 . 2040602 . free .
• SenGupta DN, Zmudzka BZ, Kumar P, Cobianchi F, Skowronski J, Wilson SH . Sequence of human DNA polymerase beta mRNA obtained through cDNA cloning . Biochemical and Biophysical Research Communications . 136 . 1 . 341–7 . April 1986 . 2423078 . 10.1016/0006-291X(86)90916-2 .
• Zmudzka BZ, Fornace A, Collins J, Wilson SH . Characterization of DNA polymerase beta mRNA: cell-cycle and growth response in cultured human cells . Nucleic Acids Research . 16 . 20 . 9587–96 . October 1988 . 2460824 . 338765 . 10.1093/nar/16.20.9587 .
• Widen SG, Kedar P, Wilson SH . Human beta-polymerase gene. Structure of the 5'-flanking region and active promoter . The Journal of Biological Chemistry . 263 . 32 . 16992–8 . November 1988 . 10.1016/S0021-9258(18)37488-X . 3182828 . free .
• Abbotts J, SenGupta DN, Zmudzka B, Widen SG, Notario V, Wilson SH . Expression of human DNA polymerase beta in Escherichia coli and characterization of the recombinant enzyme . Biochemistry . 27 . 3 . 901–9 . February 1988 . 3284575 . 10.1021/bi00403a010 .
• Dobashi Y, Kubota Y, Shuin T, Torigoe S, Yao M, Hosaka M . Polymorphisms in the human DNA polymerase beta gene . Human Genetics . 95 . 4 . 389–90 . April 1995 . 7705833 . 10.1007/bf00208961 . 22658070 .
• Chyan YJ, Ackerman S, Shepherd NS, McBride OW, Widen SG, Wilson SH, Wood TG . The human DNA polymerase beta gene structure. Evidence of alternative splicing in gene expression . Nucleic Acids Research . 22 . 14 . 2719–25 . July 1994 . 7914364 . 308239 . 10.1093/nar/22.14.2719 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Chang M, Burmer GC, Sweasy J, Loeb LA, Edelhoff S, Disteche CM, Yu CE, Anderson L, Oshima J, Nakura J . 6 . Evidence against DNA polymerase beta as a candidate gene for Werner syndrome . Human Genetics . 93 . 5 . 507–12 . May 1994 . 8168825 . 10.1007/bf00202813 . 34824853 .
• Chyan YJ, Strauss PR, Wood TG, Wilson SH . Identification of novel mRNA isoforms for human DNA polymerase beta . DNA and Cell Biology . 15 . 8 . 653–9 . August 1996 . 8769567 . 10.1089/dna.1996.15.653 .
• Pelletier H, Sawaya MR, Wolfle W, Wilson SH, Kraut J . Crystal structures of human DNA polymerase beta complexed with DNA: implications for catalytic mechanism, processivity, and fidelity . Biochemistry . 35 . 39 . 12742–61 . October 1996 . 8841118 . 10.1021/bi952955d .
• Pelletier H, Sawaya MR, Wolfle W, Wilson SH, Kraut J . A structural basis for metal ion mutagenicity and nucleotide selectivity in human DNA polymerase beta . Biochemistry . 35 . 39 . 12762–77 . October 1996 . 8841119 . 10.1021/bi9529566 .
• Pelletier H, Sawaya MR . 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 . October 1996 . 8841120 . 10.1021/bi960790i .
• Kubota Y, Nash RA, Klungland A, Schär P, Barnes DE, Lindahl T . 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 . December 1996 . 8978692 . 452490 . 10.1002/j.1460-2075.1996.tb01056.x .
• Bennett RA, Wilson DM, Wong D, Demple B . 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 . July 1997 . 9207062 . 23779 . 10.1073/pnas.94.14.7166 . 1997PNAS...94.7166B . free .
• Sawaya MR, Prasad R, Wilson SH, Kraut J, Pelletier H . Crystal structures of human DNA polymerase beta complexed with gapped and nicked DNA: evidence for an induced fit mechanism . Biochemistry . 36 . 37 . 11205–15 . September 1997 . 9287163 . 10.1021/bi9703812 .
• Bhattacharyya N, Banerjee S . 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 . September 1997 . 9294209 . 23361 . 10.1073/pnas.94.19.10324 . 1997PNAS...9410324B . free .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Tan XH, Zhao M, Pan KF, Dong Y, Dong B, Feng GJ, Jia G, Lu YY . 6 . Frequent mutation related with overexpression of DNA polymerase beta in primary tumors and precancerous lesions of human stomach . Cancer Letters . 220 . 1 . 101–14 . March 2005 . 15737693 . 10.1016/j.canlet.2004.07.049 .

External links

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

Notes and References

1. Web site: NCBI Gene: DNA polymerase beta.
2. 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 . 6 . DNA polymerase β: A missing link of the base excision repair machinery in mammalian mitochondria . DNA Repair . 60 . 77–88 . December 2017 . 29100041 . 5919216 . 10.1016/j.dnarep.2017.10.011 .
3. Subba Rao K, Martin GM, Loeb LA . Fidelity of DNA polymerase-beta in neurons from young and very aged mice . Journal of Neurochemistry . 45 . 4 . 1273–8 . October 1985 . 3161998 . 10.1111/j.1471-4159.1985.tb05553.x . 84448241 .
4. Orgel LE . Ageing of clones of mammalian cells . Nature . 243 . 5408 . 441–5 . June 1973 . 4591306 . 10.1038/243441a0 . 1973Natur.243..441O . 4153800 .
5. Cabelof DC, Raffoul JJ, Yanamadala S, Ganir C, Guo Z, Heydari AR . Attenuation of DNA polymerase beta-dependent base excision repair and increased DMS-induced mutagenicity in aged mice . Mutation Research . 500 . 1–2 . 135–45 . March 2002 . 11890943 . 3339152 . 10.1016/s0027-5107(02)00003-9 .
6. Book: Bernstein C, Bernstein H . 1991 . Aging, Sex, and DNA Repair. . Academic Press . San Diego . 0-12-092860-4 . 46–60 .
7. Canitrot Y, Cazaux C, Fréchet M, Bouayadi K, Lesca C, Salles B, Hoffmann JS . 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 . October 1998 . 9770529 . 22874 . 10.1073/pnas.95.21.12586 . 1998PNAS...9512586C . free .
8. 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 . 6 . Deregulated DNA polymerase beta induces chromosome instability and tumorigenesis . Cancer Research . 62 . 12 . 3511–4 . June 2002 . 12067997 .
9. Bergoglio V, Canitrot Y, Hogarth L, Minto L, Howell SB, Cazaux C, Hoffmann JS . Enhanced expression and activity of DNA polymerase beta in human ovarian tumor cells: impact on sensitivity towards antitumor agents . Oncogene . 20 . 43 . 6181–7 . September 2001 . 11593426 . 10.1038/sj.onc.1204743 . 30039904 .
10. Srivastava DK, Husain I, Arteaga CL, Wilson SH . DNA polymerase beta expression differences in selected human tumors and cell lines . Carcinogenesis . 20 . 6 . 1049–54 . June 1999 . 10357787 . 10.1093/carcin/20.6.1049 . free .
11. He F, Yang XP, Srivastava DK, Wilson SH . 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 . January 2003 . 12674496 . 10.1515/BC.2003.003 . 33798724 .
12. Narayan S, He F, Wilson SH . 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 . August 1996 . 8702497 . 10.1074/jbc.271.31.18508 . free .
13. Sarnowska E, Grzybowska EA, Sobczak K, Konopinski R, Wilczynska A, Szwarc M, Sarnowski TJ, Krzyzosiak WJ, Siedlecki JA . 6 . 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 . 2007 . 17704138 . 2018635 . 10.1093/nar/gkm502 .
14. Whitehouse CJ, Taylor RM, Thistlethwaite A, Zhang H, Karimi-Busheri F, Lasko DD, Weinfeld M, Caldecott KW . 6 . XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair . Cell . 104 . 1 . 107–17 . January 2001 . 11163244 . 10.1016/S0092-8674(01)00195-7 . 1487128 . free .
15. Wang L, Bhattacharyya N, Chelsea DM, Escobar PF, Banerjee S . A novel nuclear protein, MGC5306 interacts with DNA polymerase beta and has a potential role in cellular phenotype . Cancer Research . 64 . 21 . 7673–7 . November 2004 . 15520167 . 10.1158/0008-5472.CAN-04-2801 . 35569215 .
16. Fan J, Otterlei M, Wong HK, Tomkinson AE, Wilson DM . XRCC1 co-localizes and physically interacts with PCNA . Nucleic Acids Research . 32 . 7 . 2193–201 . 2004 . 15107487 . 407833 . 10.1093/nar/gkh556 .
17. Kubota Y, Nash RA, Klungland A, Schär P, Barnes DE, Lindahl T . 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 . December 1996 . 8978692 . 452490 . 10.1002/j.1460-2075.1996.tb01056.x .
18. Bhattacharyya N, Banerjee S . A novel role of XRCC1 in the functions of a DNA polymerase beta variant . Biochemistry . 40 . 30 . 9005–13 . July 2001 . 11467963 . 10.1021/bi0028789 .