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DNA damage
mutagens
Normal DNA
DNA mutation
DNA repair
In
fertile
Cell
death
Defect of
metabolism
Defect of Cell
growth regulation
Cancer
evolution
polymorphism
Inborn
error
Kerusakan DNA
Penyebab
Jenis kerusakan
Mutagen Kimiawi :
Ni
Be
Asbes (kanker paru)
Bahan pengalkil : vynil khlorida
mustard nitrogen
Nitrosurea & nitrosamin
Zat warna azo
Hidrokarbon polisiklik
Berbagai produk mikroba
Berbagai produk jamur
Hormon dietilstilbestrol (Kanker vagina &
testis)
Naftilamin-
Mutagen biologi
Virus DNA :
SV40,
Adenovirus,
Virus polioma,
Virus Herpes
Mutagen fisikal
Sinar-X
Sinar -
Sinar ultraviolet dg pj glb 320
nm
Depurination
Deamination of bases
Thymine dimer
DNA Repair
The sites on each nucleotide that are known to be modified by spontaneous oxidative
damage (red arrows), hydrolytic attack (blue arrows), and uncontrolled methylation by
the methyl group donor S-adenosylmethionine (green arrows) are shown, with the width
of each arrow indicating the relative frequency of each event.
(After T. Lindahl, Nature 362:709715, 1993. Macmillan Magazines Ltd.)
These two reactions are the most frequent spontaneous chemical reactions known to create serious DNA
damage in cells. Depurination can release guanine (shown here), as well as adenine, from DNA. The major
type of deamination reaction (shown here) converts cytosine to an altered DNA base, uracil, but
deamination occurs on other bases as well. These reactions take place on double-helical DNA; for
convenience, only one strand is shown.
Thymine dimer
The deamination of
DNA nucleotides.
In each case the oxygen atom that is added in
this reaction with water is colored red.
(A) The spontaneous deamination products of
A and G are recognizable as unnatural when
they occur in DNA and thus are readily
recognized and repaired.
The deamination of C to U was previously
illustrated in Figure 5-47; T has no amino
group to deaminate.
(B) About 3% of the C nucleotides in
vertebrate DNAs are methylated to help in
controlling gene expression (discussed in
Chapter 7).
When these 5-methyl C nucleotides are
accidentally deaminated, they form the natural
nucleotide T.
This T would be paired with a G on the
opposite strand, forming a mismatched base
pair.
DNA glycosylase
At least 8 DNA glycosylases in human.
UNG = uracyl DNA glycosylase remove U from DNA
Depurination
Apurinic Endonuclease
Excision repair
Basic steps : recognize damage
Remove damage by excising part of one strand
Resynthesize to fill gap; genetic information from other strand used
Ligate to restore continuity of DNA
Base excision repair:
Glycosylase remove base, leaves
backbone intack
AP endonuclease cuts backsbone,
AP lyase removes sugar
DNA polymerase fills the gap
DNA ligase seals the nick
Enzymatic demethylation
Alkylating bases are mutagenic.
Methyl guanine basepair with T rather than C. Replication this basepair
lead to mutation.
Glycosylases recognizes the the methylated bases, trigger base
excision repair.
Cell also has special protein that recognize methyl guanine in DNA, and
directly remove the methyl group by enzyme methyl guanine methyl
transsferase (MGMT), transfer it to cystein in their protein, make the
protein inactive and degraded through the ubiquitin proteolytic pathway.
Photoreactivation
Repair cyclobutane pyrimidine dimers,
Apoptosi
s in DNA
damage
Mutation
Frameshift mutation
Frameshift mutation
Segregation of mutant
PHENOTYPE
ENZYME OR PROCESS
AFFECTED
colon cancer
mismatch repair
Xeroderma
pigmentosum (XP)
groups A -G
nucleotide excision-repair
XP variant
cellular UV sensitivity
BRCA-2
repair by homologous
recombination
Werner syndrome
Bloom syndrome
congenital abnormalities,
leukemia, genome instability
46 BR patient
hypersensitivity to DNA-damaging
agents, genome instability
DNA ligase I
Semoga
bermanfa
at