Cell Nucleus Biogenesis, Structure and Function
387
Errors are not uncommon, but very ef-
fective proofreading and postreplicative
mismatch repair activities ensure that
the genetic information encoded in the
parental DNA strand is preserved during
DNA replication.
In addition to this, numerous sources
of DNA damage have the potential to
generate lesions that will ultimately give
rise to mutations in DNA (Table 2). Classes
of DNA damage include the following:
1. Chemical or oxidative damage that
might lead to base modiFcation or base
excision. ±or example, spontaneous hy-
drolysis can cause deamination (e.g.
turning cytosine to uracil) and depuri-
nation (e.g. removing a guanine base).
2. Ultraviolet
light
induces
a
photo-
chemical cyclization between adjacent
thymine/thymine or thymine/cytosine
residues.
3. Ultraviolet light and other types of
radiation can induce single- and double-
strand breaks in the DNA backbone.
4. Some chemicals can interact with the
DNA to form bulky adducts or interca-
late into the DNA. Both processes are
potentially mutagenic.
Together these insults ensure that the
DNA within each mammalian cell will ex-
perience many thousands of lesions every
day. To cope with this, cells employ a vari-
ety of repair mechanisms (Table 2). In each
case, the efFciency of the process relies on
thefactthatthestructureofDNAprovides
a template for repair. The general mech-
anism of DNA repair involves three basic
steps. The Frst involves the recognition
of damage and excision of the damage by
DNA repair nucleases. A DNA polymerase
can then bind to the free 3
0
-OH end of
the cut DNA and Fll the gap using the
complementary DNA strand as template.
±inally, the nick that remains in the DNA
backbone following incorporation of the
new base(s) is sealed by the DNA ligase.
Depurination is the
most common
form of a potentially mutagenic lesion
Tab. 2
DNA repair mechanisms and damage types.
Mechanism
Damage
Repair proteins involved
Exonuclease of DNA
polymerase
Inaccuracies during DNA
replication (proofreading)
DNA pol
δ
/
ε
,ligase
Base-mismatch repair
Small adducts
Insertions/deletions
Oxidative damage
MSH6/3-MSH2 (dimer)
PMS1, MLH1, PCNA
DNA pol
δ
,ligase
Nucleotide excision repair
Bulky adducts
UV cross-links
XPA – XPG, RPA, TFIIH
ERCC1, DNApol
δ
/
ε
PCNA, ligase
Base excision repair
Abasic sites
Deamination
Oxidative damage
Alkylations
N-glycosidases
AP endonuclease
DNApol
β
,DNAligase
Homologous
recombination
Strand breaks
RAD51, other RAD proteins RPA,
DNApol, ligase
p53, BRCA1, BRCA2
DNA end-joining
Strand breaks
Ku70, XRCC5, DNAPK p53, ATM
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