Definition: Base excision repair (BER) protects against damage to DNA from reactive oxygen species, methylation, deamination, hydroxylation and other by-products of cellular metabolism.
ROS-associated DNA lesions
Reactive oxygen species (ROS) from endogenous and environmental sources induce oxidative damage to DNA, and are a threat to the integrity of genome. This oxidative DNA damage can be restored by the base excision repair (BER) pathway that is conserved from bacteria to humans.
Active oxygen species in the nucleotide pool of the cell can produce 8-oxo-dGTP (8-oxo-7,8-dihydrodeoxyguanosine triphosphate), which can then be incorporated into cellular DNA. Human cells contain enzyme activity that hydrolyzes 8-oxo-dGTP to 8-oxo-dGMP, thereby preventing occurrence of mutations caused by misincorporation.
This oxidative DNA damage is restored by the base excision repair (BER) pathway that is conserved from bacteria to humans and is initiated by DNA glycosylases, which simply remove the aberrant base from the DNA backbone by hydrolyzing the N-glycosidic bond (monofunctional DNA glycosylase), or further catalyze the incision of a resulting abasic site (bifunctional DNA glycosylase).
BER system
In eukaryotic cells, DNA polymerase beta (POLB) performs base excision repair (BER) required for DNA maintenance, replication, recombination, and drug resistance. Two important enzymatic steps in mammalian BER are contributed by POLB: DNA resynthesis of the repair patch and lyase removal of the 5-prime-deoxyribose phosphate.
BER is initiated by a class of DNA-repair-specific enzymes - DNA glycosylases - each of which recognizes a single or a small subset of chemically altered or inappropriate bases.
For example, an enzyme called uracil DNA-glycosylase specifically recognizes uracil as an inappropriate base in DNA and catalyses hydrolysis of the N-glycosyl bond that links the uracil base to the deoxyribose-phosphate backbone of DNA.
Uracil is thus excised from the genome as a free base, leaving a site of base loss in the DNA - an apyrimidinic site in the case of uracil removal, or an apurinic site when a purine is lost. These so-called AP (or abasic) sites are repaired by a further series of biochemical events.
Pathway
apurinic/apyrimidinic endonuclease/redox factor 1 (APE/ref1)
Pathology
- BER DNA glycosylase MYH biallelic mutations in autosomal recessive syndrome of adenomatous colorectal polyposis
See also
References
Farrington SM, Tenesa A, Barnetson R, Wiltshire A, Prendergast J, Porteous M, Campbell H, Dunlop MG. Germline Susceptibility to Colorectal Cancer Due to Base-Excision Repair Gene Defects. Am J Hum Genet. 2005 May 3;77(1). PMID: 15871140
Fortini P, Pascucci B, Parlanti E, D’Errico M, Simonelli V, Dogliotti E. The base excision repair: mechanisms and its relevance for cancer susceptibility. Biochimie. 2003 Nov;85(11):1053-71. PMID: 14726013
Cheadle JP, Sampson JR. Exposing the MYtH about base excision repair and human inherited disease. Hum Mol Genet. 2003 Oct 15;12 Spec No 2:R159-65. PMID: 12915454