DNA polymerase beta

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. 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. This finding was considered to provide evidence against the error catastrophe theory of aging.

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. 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. Cabelof et al. 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.

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. 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. 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 and XRCC1.

References

References

1. "NCBI Gene: DNA polymerase beta".
2. (December 2017). "DNA polymerase β: A missing link of the base excision repair machinery in mammalian mitochondria". DNA Repair.
3. (October 1985). "Fidelity of DNA polymerase-beta in neurons from young and very aged mice". Journal of Neurochemistry.
4. (June 1973). "Ageing of clones of mammalian cells". Nature.
5. (March 2002). "Attenuation of DNA polymerase beta-dependent base excision repair and increased DMS-induced mutagenicity in aged mice". Mutation Research.
6. (1991). "Aging, Sex, and DNA Repair.". Academic Press.
7. (October 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.
8. (June 2002). "Deregulated DNA polymerase beta induces chromosome instability and tumorigenesis". Cancer Research.
9. (September 2001). "Enhanced expression and activity of DNA polymerase beta in human ovarian tumor cells: impact on sensitivity towards antitumor agents". Oncogene.
10. (June 1999). "DNA polymerase beta expression differences in selected human tumors and cell lines". Carcinogenesis.
11. (January 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.
12. (August 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.
13. (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.
14. (January 2001). "XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair". Cell.
15. (November 2004). "A novel nuclear protein, MGC5306 interacts with DNA polymerase beta and has a potential role in cellular phenotype". Cancer Research.
16. (2004). "XRCC1 co-localizes and physically interacts with PCNA". Nucleic Acids Research.
17. (December 1996). "Reconstitution of DNA base excision-repair with purified human proteins: interaction between DNA polymerase beta and the XRCC1 protein". The EMBO Journal.
18. (July 2001). "A novel role of XRCC1 in the functions of a DNA polymerase beta variant". Biochemistry.