Biology Reference
In-Depth Information
how BER is regulated to allow for efficient and accurate repair of many types of
DNA base damage in both nuclear and mitochondrial genomes. Regulation of
BER has been proposed to occur at multiple, different levels including tran-
scription, posttranslational modification, protein-protein interactions, and pro-
tein localization; however, none of these regulatory mechanisms characterized
thus far affect a large spectrum of BER proteins. This chapter discusses a
recently discovered mode of BER regulation defined in budding yeast cells that
involves mobilization of DNA repair proteins to DNA-containing organelles in
response to genotoxic stress.
I. Base Excision Repair
A. Requirements and Limitations of Base
Excision Repair
There are more than 100,000 oxidative lesions and 200,000 apurinic/apyr-
imidinic (AP) sites generated per human cell per day.
1,2
It is the primary
responsibility of the base excision repair (BER) pathway to police cellular DNA
for such endogenous DNA damage and to efficiently repair these lesions or face
the accumulation of mutations and eventual loss of cell viability or oncogenic
transformation. Furthermore, a cell must also be prepared to respond to any
acute stresses such as those caused by oxidative bursts during infections or
chronic stresses caused by the accumulation of mutations, which occurs during
aging. Both infection and aging raise the level of DNA damage and require
mechanisms of regulation to appropriately increase DNA repair capacity.
3,4
Organisms have evolved partially redundant sets of DNA repair pathways
to manage a wide range of damaged DNA, the BER pathway being one of
them. Much of our understanding about the inner workings of eukaryotic BER
pathways comes from knowledge obtained through work performed in the
budding yeast,
Saccharomyces cerevisiae
. Numerous studies reveal that inves-
tigation of this evolutionarily conserved pathway in yeast provides valuable
insight into the process in humans.
5,6
Through studies done in yeast in part, we
appreciate that recognition of base damage by BER proteins is partially redun-
dant with certain
N
-glycosylases having complementary base specificities, that
BER proteins are present at relatively low copy numbers per cell, and finally,
that BER proteins localize to nuclei, mitochondria, or both.
7
The relative
expression level of each protein in the BER pathway is particularly important
when we consider that the excision of damaged bases by
N
-glycosylases often
generates mutagenic intermediates. If such intermediates are not processed
and repaired, mutations may occur, resulting in cell death or other deleterious
consequences.
8-10
As such, to ensure the maintenance of genome stability and
