| 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 |
DNA polymerase beta, also known as POLB, is an enzyme present in eukaryotes. In humans, it is encoded by the POLB gene. [4]
In eukaryotic cells, DNA polymerase beta (POLB) performs base excision repair (BER) required for DNA maintenance, replication, recombination, and drug resistance. [4]
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. [5] POLB thus has a key role in maintaining the stability of the mitochondrial genome. [5]
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. [6] This finding was considered to provide evidence against the error catastrophe theory of aging. [6] [7]
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. [8] 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. [9] Cabelof et al. [8] 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.
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. [10] [11] [12] [13]
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. [14] [15] 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. [16] 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.
DNA polymerase beta has been shown to interact with PNKP [17] and XRCC1. [18] [19] [20] [21]
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. [22] Male and female animals underwent a standardized phenotypic screen [23] to determine the effects of deletion. [24] [25] [26] [27] Additional screens performed: In-depth immunological phenotyping [28]
| Characteristic | Phenotype |
|---|---|
| All data available at. [23] [28] { | |
| 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 |
A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create two identical DNA duplexes from a single original DNA duplex. During this process, DNA polymerase "reads" the existing DNA strands to create two new strands that match the existing ones. These enzymes catalyze the chemical reaction
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encodes its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur, including double-strand breaks and DNA crosslinkages. This can eventually lead to malignant tumors, or cancer as per the two-hit hypothesis.
Nucleotide excision repair is a DNA repair mechanism. DNA damage occurs constantly because of chemicals, radiation and other mutagens. Three excision repair pathways exist to repair single stranded DNA damage: Nucleotide excision repair (NER), base excision repair (BER), and DNA mismatch repair (MMR). While the BER pathway can recognize specific non-bulky lesions in DNA, it can correct only damaged bases that are removed by specific glycosylases. Similarly, the MMR pathway only targets mismatched Watson-Crick base pairs.
Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from the genome. The related nucleotide excision repair pathway repairs bulky helix-distorting lesions. BER is important for removing damaged bases that could otherwise cause mutations by mispairing or lead to breaks in DNA during replication. BER is initiated by DNA glycosylases, which recognize and remove specific damaged or inappropriate bases, forming AP sites. These are then cleaved by an AP endonuclease. The resulting single-strand break can then be processed by either short-patch or long-patch BER.
MUTYH is a human gene that encodes a DNA glycosylase, MUTYH glycosylase. It is involved in oxidative DNA damage repair and is part of the base excision repair pathway. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a common form of oxidative DNA damage.
XPB is an ATP-dependent DNA helicase in humans that is a part of the TFIIH transcription factor complex.
ERCC2, or XPD is a protein involved in transcription-coupled nucleotide excision repair.
Transcription factor II H (TFIIH) is an important protein complex, having roles in transcription of various protein-coding genes and DNA nucleotide excision repair (NER) pathways. TFIIH first came to light in 1989 when general transcription factor-δ or basic transcription factor 2 was characterized as an indispensable transcription factor in vitro. This factor was also isolated from yeast and finally named TFIIH in 1992.
DNA repair protein XRCC1, also known as X-ray repair cross-complementing protein 1, is a protein that in humans is encoded by the XRCC1 gene. XRCC1 is involved in DNA repair, where it complexes with DNA ligase III.
DNA-(apurinic or apyrimidinic site) lyase is an enzyme that in humans is encoded by the APEX1 gene.
DNA excision repair protein ERCC-1 is a protein that in humans is encoded by the ERCC1 gene. Together with ERCC4, ERCC1 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination.
DNA excision repair protein ERCC-6 is a protein that in humans is encoded by the ERCC6 gene. The ERCC6 gene is located on the long arm of chromosome 10 at position 11.23.
DNA repair protein complementing XP-G cells is a protein that in humans is encoded by the ERCC5 gene.
DNA polymerase lambda, also known as Pol λ, is an enzyme found in all eukaryotes. In humans, it is encoded by the POLL gene.
DNA excision repair protein ERCC-8 is a protein that in humans is encoded by the ERCC8 gene.
TFIIA-alpha and beta-like factor is a protein that in humans is encoded by the GTF2A1L gene.
Poly [ADP-ribose] polymerase 2 is an enzyme that in humans is encoded by the PARP2 gene. It is one of the PARP family of enzymes.
Zinc finger protein 143 is a protein that in humans is encoded by the ZNF143 gene.
The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although both mitochondrial and nuclear DNA damage can contribute to aging, nuclear DNA is the main subject of this analysis. Nuclear DNA damage can contribute to aging either indirectly or directly.
DNA ligase 3 is an enzyme that, in humans, is encoded by the LIG3 gene. The human LIG3 gene encodes ATP-dependent DNA ligases that seal interruptions in the phosphodiester backbone of duplex DNA.
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