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REPAIR
MAHAYU DEWI ARIANI
BAGIAN BIOLOGI
FAKULTAS KEDOKTERAN
UNIVERSITAS DIPONEGORO
DNA Damage
1000 - 1000000 molecular lesions/cell/day
impede a cell's ability to carry out its function
and appreciably increase the likelihood of
tumor formation.
physical abnormalities in the DNA, such as
single and double strand breaks
recognized by enzymes
DNA Damage vs
Mutation
Mutation:
change in the base sequence of the DNA.
cannot be recognized by enzymes
once the base change is present in both DNA
strands
cannot be repaired
DNA damages often cause errors of DNA
synthesis during replication or repair and these
errors are a major source of mutation.
Sources of damage
endogenous damage
attack by reactive oxygen species
exogenous damage
external agents such as
ds DNA Break
Mismatch
C-U deamination
ss Break
Thymidine dimer
Covalent X-linking
AP site
Consequences of DNA
damage
DNA DAMAGE
SHORT-TERM CONSEQUENCES
PHYSIOLOGICAL
DYSFUNCTION
Decreased cellular
proliferation
CELL DEATH
Genomic
instability
Defective signalling
pathways
LONG-TERM CONSEQUENCES
Ageing
Cancer
Disease
DNA Repair
a collection of processes by which a cell identifies
and corrects damage to the DNA molecules
that encode its genome
Mismatch repair
Double-strand breaks
Non-Homolog End Joining repair (NHEJ)
Homologous Recombination repair
BER enzymes:
E.coli
S. cerevisiae
H. sapiens
MutM (fpg)
hOGG1
yOGG1&2
_ _ _ _
_ _ _ _
hMPG
hNEIL1
BER enzymes:
S. cerevisiae
H. sapiens
Ntg1&2
_ _ _ _ _
_ _ _ _ _
_ _ _ _ _
hNTHL1
hNEIL1-3
_ _ _ _
hTDG
BER
Long patch
Short patch
AP endonuclease
(HAP1, REF1)
Gap filling
PCNA
DNA pol
DNA polymerase
LIG3
DNA ligase
Human NER
XPB
XPD
XPA
XPC
XPG
XPF
:Part of endonuclease
(5' incision)
Rad1/10
Rad2 inS.
cerevisiae
Mismatched
bases.
3'
T
5'
T
5'
OH 3'
5'
T
5'
T
1
G
OH
OH
3'
Mismatch
Answer
Repaired Mismatch
NHEJ
DNA Ligase IV, a specialized DNA
ligase that forms a complex with
the cofactor XRCC4, directly joins
the two ends
To guide accurate repair, NHEJ
relies on short homologous
sequences called microhomologies
important before the cell has
replicated its DNA
The end-joining pathway of ds
break repair is mutagenic, because
it removes several base pairs at
the break site.
Homologous
Recombination
requires the presence of an identical or nearly identical
sequence to be used as a template for repair of the
break.
This pathway allows a damaged chromosome to be
repaired using a sister chromatid (G2 after DNA
replication) or a homologous chromosome as a
template.
DSBs caused by the replication machinery attempting
to synthesize across a single-strand break or
unrepaired lesion are typically repaired by
recombination.
Homologous
recombination in
eukaryotes
1. Ds break
2. dsDNA activates ATM kinase, which
activates exo-nucleases that create ss 3
ends. In a reaction that depends on
BRCA 1 & 2, Rad51 coats the ss 3 ends.
3. Rad51 and friends pair the 3 end with
the sister chromatid.
4. DNA polymerase elongates.
5. Pairing of the new DNA bridges the
gap.
6. The gap is filled and ligated.
Thank
you..