DNA polymerase


DNA polymerase
3D structure of the DNA-binding helix-turn-helix motifs in human DNA polymerase beta

A DNA polymerase is an enzyme that helps catalyze in the polymerization of deoxyribonucleotides into a DNA strand. DNA polymerases are best known for their feedback role in DNA replication, in which the polymerase "reads" an intact DNA strand as a template and uses it to synthesize the new strand. This process copies a piece of DNA. The newly polymerized molecule is complementary to the template strand and identical to the template's original partner strand. DNA polymerases use magnesium ions as cofactors. Human DNA polymerases are 900-1000 amino acids long.

Contents

Function

DNA polymerase with proofreading ability

DNA polymerase can add free nucleotides to only the 3' end of the newly forming strand. This results in elongation of the new strand in a 5'-3' direction. No known DNA polymerase is able to begin a new chain (de novo). DNA polymerase can add a nucleotide onto only a preexisting 3'-OH group, and, therefore, needs a primer at which it can add the first nucleotide. Primers consist of RNA and/or DNA bases. In DNA replication, the first two bases are always RNA, and are synthesized by another enzyme called primase. An enzyme known as a helicase is required to unwind DNA from a double-strand structure to a single-strand structure to facilitate replication of each strand consistent with the semiconservative model of DNA replication.

Error correction is a property of some, but not all, DNA polymerases. This process corrects mistakes in newly synthesized DNA. When an incorrect base pair is recognized, DNA polymerase reverses its direction by one base pair of DNA. The 3'-5' exonuclease activity of the enzyme allows the incorrect base pair to be excised (this activity is known as proofreading). Following base excision, the polymerase can re-insert the correct base and replication can continue.

Various DNA polymerases are extensively used in molecular biology experiments.

Variation across species

DNA polymerases have highly conserved structure, which means that their overall catalytic subunits vary, on a whole, very little from species to species. Conserved structures usually indicate important, irreplaceable functions of the cell, the maintenance of which provides evolutionary advantages.

Some viruses also encode special DNA polymerases, such as Hepatitis B virus DNA polymerase. These may selectively replicate viral DNA through a variety of mechanisms. Retroviruses encode an unusual DNA polymerase called reverse transcriptase, which is an RNA-dependent DNA polymerase (RdDp). It polymerizes DNA from a template of RNA.

DNA polymerase families

DNA polymerase family A
PDB 2hht EBI.jpg
c:o6-methyl-guanine pair in the polymerase-2 basepair position
Identifiers
Symbol DNA_pol_A
Pfam PF00476
InterPro IPR001098
PROSITE PDOC00412
SCOP 1dpi
DNA polymerase family B
PDB 2dy4 EBI.jpg
crystal structure of rb69 gp43 in complex with dna containing thymine glycol
Identifiers
Symbol DNA_pol_B
Pfam PF00136
Pfam clan CL0194
InterPro IPR006134
PROSITE PDOC00107
SCOP 1noy
DNA polymerase type B, organellar and viral
PDB 1xhz EBI.jpg
phi29 dna polymerase, orthorhombic crystal form, ssdna complex
Identifiers
Symbol DNA_pol_B_2
Pfam PF03175
Pfam clan CL0194
InterPro IPR004868

Based on sequence homology, DNA polymerases can be further subdivided into seven different families: A, B, C, D, X, Y, and RT.

Family A

Polymerases contain both replicative and repair polymerases. Replicative members from this family include the extensively studied T7 DNA polymerase, as well as the eukaryotic mitochondrial DNA Polymerase γ. Among the repair polymerases are Escherichia coli DNA pol I, Thermus aquaticus pol I, and Bacillus stearothermophilus pol I. These repair polymerases are involved in excision repair and processing of Okazaki fragments generated during lagging strand synthesis.

Family B

B family polymerases are involved in DNA repair and replication. These include; Pol II (bacterial), Pol B (archaebacterial), and Pol α, δ, and ε (eukaryotic). Pol ζ another B family polymerase, is made of two subunits Rev3 and Rev7 and is involved in translesion synthesis. Pol ζ is unique in that it can extend primers with terminal mismatches.

Family C

Polymerases are the primary bacterial chromosomal replicative enzymes. DNA Polymerase III alpha subunit from E. coli is the catalytic subunit [1] and possesses no known nuclease activity. A separate subunit, the epsilon subunit, possesses the 3'-5' exonuclease activity used for editing during chromosomal replication. Recent research has classified Family C polymerases as a subcategory of Family X[citation needed].

Family D

Polymerases are still not very well characterized. All known examples are found in the Euryarchaeota subdomain of Archaea and are thought to be replicative polymerases.

Family X

Contains the well-known eukaryotic polymerase pol β, as well as other eukaryotic polymerases such as pol σ, pol λ, pol μ, and terminal deoxynucleotidyl transferase (TdT). Pol β is required for short-patch base excision repair, a DNA repair pathway that is essential for repairing alkylated or oxidised bases as well as abasic sites. Pol λ and Pol μ are involved in non-homologous end-joining, a mechanism for rejoining DNA double-strand breaks. TdT is expressed only in lymphoid tissue, and adds "n nucleotides" to double-strand breaks formed during V(D)J recombination to promote immunological diversity. The yeast Saccharomyces cerevisiae has only one Pol X polymerase, Pol IV, which is involved in non-homologous end-joining.

Family Y

Y Polymerases differ from others in having a low fidelity on undamaged templates and in their ability to replicate through damaged DNA, known as translesion synthesis (TLS). Members of this family are hence called translesion synthesis polymerases. Depending on the lesion, TLS polymerases can bypass the damage in an error-free or error-prone fashion, the latter resulting in elevated mutagenesis. Xeroderma pigmentosum variant (XPV) patients for instance have mutations in the gene encoding Pol η (eta), which is error-free for UV-lesions. In XPV patients, alternative error-prone polymerases, e.g., Pol ζ (zeta) (polymerase ζ is a B Family polymerase a complex of the catalytic subunit REV3L with Rev7, which associates with Rev1[2]), are thought to be involved in mistakes that result in the cancer predisposition of these patients. Other members in humans are Pol ι (iota), Pol κ (kappa), and Rev1 (terminal deoxycytidyl transferase). In E. coli, two TLS polymerases, Pol IV (DINB) and Pol V (UmuD'2C), are known.

Family RT

The reverse transcriptase family contains examples from both retroviruses and eukaryotic polymerases. The eukaryotic polymerases are usually restricted to telomerases. These polymerases use an RNA template to synthesize the DNA strand.

Prokaryotic DNA polymerases

Bacteria have 5 known DNA polymerases.

Eukaryotic DNA polymerases

Eukaryotes have at least 15 DNA Polymerases.[3]

See also

References

  1. ^ Lamers, M.; Georgescu, R.; Lee, S.; O'Donnell, M.; Kuriyan, J. (2006). "Crystal structure of the catalytic alpha subunit of E. coli replicative DNA polymerase III". Cell 126 (5): 881–892. doi:10.1016/j.cell.2006.07.028. PMID 16959568.  edit
  2. ^ Gan GN; Wittschieben JP; Wittschieben BØ; Wood RD (2008). "DNA polymerase zeta (pol zeta) in higher eukaryotes". Cell Research 18 (1): 174–83. doi:10.1038/cr.2007.117. PMID 18157155. 
  3. ^ I. Hubscher, U.; Maga, G.; Spadari, S. (2002). "Eukaryotic DNA polymerases". Annual Review of Biochemistry 71: 133–63. doi:10.1146/annurev.biochem.71.090501.150041. PMID 12045093. 

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