Thursday, March 17, 2011

The Secret of Life

DNA polymerase was first discovered in 1956 by Arthur Kornberg and his colleagues and was the first enzyme in DNA synthesis to be revealed. It was immediately coined the “eureka enzyme” and rightfully so. Now know to perform various roles in DNA replication, including synthesis of new strand, DNA repair, and proofreading, DNA polymerase’s discovery has allowed for tools such as PCR to exist and made our current understanding of DNA synthesis possible. Prior to its discovery, scientists thought DNA synthesis was too complicated of a process to understand.1
DNA polymerase in action! Image obtained from BioAP.wikispaces.com
DNA polymerase is notorious for its astounding accuracy in DNA replication. Its base selectivity and proofreading capability results in less than one mutation per genome duplication. There are currently three known DNA polymerases responsible for dividing up the work of eukaryotic nuclear genome replication. It has recently been found when DNA polymerase ϵ in humans loses its capability to correct its errors in replication the fidelity of the replicated strand is still maintained.2 This was the first piece of evidence that human DNA polymerase is more accurate than polymerase in yeast cells and is being further researched.

Not only is DNA polymerase faithful to its host, it can also repair damages in DNA. Specifically DNA polymerase III in E. coli is crucial for repairing damages caused by hydrogen peroxide, a byproduct of oxidative metabolism, and methyl methanesulfonate (MMS), an alkylating agent.3 Experiments has also shown that DNA polymerase is important in repairing DNA induced by UV damage.

Because DNA polymerase plays an essential role in DNA synthesis, mutations of the enzyme can lead to cancerous cells. Studies have been found that 30% of tumors in humans contained a mutated DNA polymerase β. When the enzyme is altered, more base substitution errors in occur in DNA replication, which may lead to cancerous cells.4 Overexpression the enzyme has also been linked to tumors. The connection between certain cancers and altered DNA polymerase β opens the door for new therapeutic treatments to be looked into.

You may be asking yourself, how is DNA polymerase capable of multiple roles in DNA synthesis? As my high school AP biology teacher drilled: structure dictates function. The structure of the enzyme resembles a hand with three distinct catalytic sites. A site for adding nucleotides to the new DNA strand, proofreading, and removal of primer all exist on this single protein. The synthesized DNA strand rests in the “palm” of the enzyme while DNA polymerase is hard at work.5 It is safe to say that life as we know it would cease to exist without DNA polymerase.

Two "versions" of DNA polymerase in E. coli (left) and Thermus aquaticus (right). Photo obtained from RCSB Protein Data Bank.

References:
1Lehman, I. R. "Discovery of DNA Polymerase." The Journal of Biological Chemistry 5 June (2003). Web. 17 Mar. 2011. <http://www.jbc.org/content/278/37/34733.full>.

2Korona, Dagmara A., Kimberly G. LeCompte, and Zachary F. Pursell. "The high fidelity and unique error signature of human DNA polymerase ε." Nucleic Acids Research 29 Oct. (2010). PubMed. Web. 17 Mar. 2011. <http://nar.oxfordjournals.org/content/early/2010/10/28/nar.gkq1034.long>.

3Hagensee, M. E., S. K. Bryan, and R. E. Moses. "DNA polymerase III requirement for repair of DNA damage caused by methyl methanesulfonate and hydrogen peroxide." Journal of Bacteriology Oct. (1987). PubMed. Web. 17 Mar. 2011. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC213829/>.

4Starcevic, D., S. Dalal, and J. B. Sweasy. "Is There a Link Between DNA Polymerase Beta and Cancer?" Cell Cycle Aug. (2004). PubMed. Web. 17 Mar. 2011. <http://www.landesbioscience.com/journals/cc/starcevicCC3-8.pdf>.

5Goodshell, David S. RCSB Protein Data Bank. N.p., Mar. 2000. Web. 17 Mar. 2000. <http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb3_2.html>.

3 comments:

  1. Great post. Thanks for sharing.Klenow (3′→ 5′ exo-) is a mesophilic dna polymerase deficient in both proofreading (3′→ 5′) and nick-translation (5′→ 3′) nuclease activities, and that displays a moderate strand displacement activity during DNA synthesis.

    ReplyDelete
  2. Great post! Thanks a lot for sharing this information. Cheers!

    klenow dna polymerase

    ReplyDelete