Deoxyribose nucleic acid, known more commonly as DNA, is the genetic material of human cells. The integrity of the bases, or nucleotides, that create the DNA sequence is important for proper cell function via the transcription of proteins. Mutations to the chemical structure of the bases caused by endogenous sources, such as oxidative damage and uracil placement in DNA, are most commonly corrected by a mechanism called base excision repair (BER). One of the most common point mutations is the addition of a methyl group to cytosine followed by deamination to thymine. Alkylation also occurs, frequently during chemotherapy during the treatment of cancers. Some of these changes can be reversed as opposed to needing base excision.
The Base Excision Repair Mechanism
The enzyme responsible for base excision repair is DNA glycosylase. A family of enzymes, DNA glycosylase occurs as several proteins that recognize specific mutations, with a number that are specific for uracil recognition and removal. After recognition of the aberrant base, the glycosylase removes the base, leaving an AP site (apurinic/apyrimidinic – meaning no nucleoside attached to the backbone). AP endonuclease then nicks the backbone, creating a 3’OH terminus that can be used by DNA polymerase, the replication machinery. DNA polymerase beta or epsilon and DNA ligase are capable of inserting and patching the DNA strand.
The Results of Impaired Base Excision Repair
Impaired repair of DNA damage can result in aberrant transcription and halt cellular replication. Cancer is one of the most well known disorders of DNA damage. There are a number of cancer types and an even larger number of genes involved in the repair pathways. Like other DNA repair pathways, mutations in the genes of the BER pathway have been associated with accumulated DNA damage and the occurrence of some cancers, including breast cancer, colorectal cancer, melanoma (skin cancer), lung cancer, and leukemia (blood cancer). There is some question though as to what extent other genetic factors contribute, such as those found to be different among ethnic subpopulations.
Long Patch Base Excision Repair
Though BER is known for repairing a single base or short patch, and NER (nucleotide excision repair) is known for excising and repairing a larger patch of damaged nucleotides, there is a phenomenon known as long patch BER. The long patch repair is in response to ionizing radiation-induced DNA damage at certain points in the cell cycle. The active glycosylases appear to be ones that can remove dihydrouracil and 8-oxoG. The BER process is similar to that of the short patch mechanism, utilizing glycosylases, AP endonuclease, and DNA polymerase. The patches are usually limited to no more than four nucleotides due to DNA ligase.
Chaudhry. Base excision repair of ionizing radiation-induced DNA damage in G1 and G2 cell cycle phases. Cancer Cell International. 7(15), 2007.
Pascucci et al. Long patch base excision repair with purified human proteins. Journal of Biological Chemistry. 274(47), 1999.