DNA repair: Base excision repair LONG patch 1.0 - Full HD
Base excision repair (BER) pathway, protects both nuclear and mitochondrial DNA from "spontaneous DNA damage", mainly generated by eactive oxigen spices (ROS) produced by the normal metabolism of the cell. The spectrum of nucleotide base lesions includes: spontaneous or enzyme-induced deamination, oxidation or alkylation.
The starrings of the BER pathway are the glycosylases enzymes. They are the DNA-damage sensors and have evolved to selectively detect different kinds of DNA insults. An important trait of the glycosylases consists in their substrate redundance, as demonstrated by mouse models lacking one glycosylase, wich triggers mild consecuences. The glycosylases can be classified as monofunctional, when, only posses the N-glycosylase function, so exclusively removes the damaged nitrogenated base of the nucleotide. When additionally has an AP-lyase activity to remove the deoxyribophosphate (dRP), generating an abasic (AP) site, they are considered as bifunctional glycosylases.
MONOFUNCTIONAL DNA Glycosylases:
MPG
UNG-1
UNG2
SMUG
MBD4
TDG
MYH
BIFUNCTIONAL DNA Glycosylases:
OGG1
NTH
NEIL-1
NEIL-2
Main steps of BER long patch:
1- A depurinized, oxydized or alkylated nucleotide base is generated spontaneously or by metabolic-generated reactive oxygen species.
2- A DNA glysosylase specifically detects the damaged nitrogenated base of the nucleotide and removes it. If the damaged DNA consist in a single-strand break (SSB), the Poly (ADP-ribose) polymerases 1 or 2 can play an important role as sensors of SSB lesions.
3- The XRCC1 protein, brings APE1 nuclease into the damage site, where will use its AP-lyase activity for cleaving the 5' extrem of the phosphodiester bond.
4- Replication factor C (FRC) reclutes PCNA and DNA polymerases δ or β. The DNA polymerase displaces from 2 to 8 nucleotides from the damaged site and at the same time polymerizes by complementarity in a PCNA depending manner.
5- Later, a flap endonuclease (FEN1) cleaves the displaced "oligonucleotide".
6- Finally, the DNA ligase I seals the de novo incorporated nucleotides.
Bibliography:
1- Gougang Xu, et al.(2008). Base excision repair, aging and health span. Mech Ageing Dev. 129: 366-382.
2- Robertson, A.B., Klungland, a., Tognes, T. and Leiros, I. (2009) Base excisioin repair: the long and short of it. Cell Mol Life Sci. 66:981-993.
3- Hedge, M.L., Hazra K.T., and Mitra, S. (2008) Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells. Cell Research. 18:27-47.