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Reparo de DNA e Mutagenese
Como os organismos vivos lidam com a instabilidade quimica do DNA?
http://www.mypureradiance.com/ppc/dna-skin-care.html
Qual a diferença entre mutação e
lesão no DNA?
Sites of oxidative damage in DNA
N
NN
N
NH2
O
HO
HHHH
ONH
N
N
O
NH2N
O
H
HHHH
O
OP
O-
O
O
H
HH
HH
N
N
NH2
OOP
O-
O
O
P
O-
O O
H
HHHH
HN
N
O
O
O
O
O
P
O-
O
P
O-
O O
CH3
sugar-phosphate backbone
adenine
guanine
cytosine
thymine
Sites of attackby •OH
Sites of attackby •OH
Reviewed in:Evans, M. D., Dizdaroglu, M. and Cooke, M. S., Mutat. Res. 567, 1-61, 2004
Products of oxidative damage to DNA bases
NH
HN
O
HNH
HN
OCH2OH
NH
HNO
NH
HN
O
H
NH
N
NH
HN
NH
NOH
NH
N
NH
HN
NH
HN
NH
N
NH
HN
O
HNH
HNO
N
N NH
NN
N NH2
NHCHO
H
N
N NH
N
HO
HN
N NH
NHN
N NH2
NHCHO
NH
HNOH
NH
HNOH
NH
HN
thymine glycol
3
5-hydroxymethyl- uracil
5,6-dihydrothymine
3
5-hydroxy-5-methyl- hydantoin
3
5-hydroxy-6-hydro- thymine
5-hydroxy-6-hydro- cytosine
5-hydroxy-6-hydro-uracil
cytosine glycol 5-hydroxycytosine
5-hydroxyuracil
5,6-dihydroxycytosine
5,6-dihydroxyuracil 5,6-dihydrouracilalloxan
8-hydroxyadenine 4,6-diamino-5-form-amidopyrimidine
8-hydroxyguanine2-hydroxyadenine 2,6-diamino-4-hydroxy-5-formamidopyrimidine
uracil glycol 5-hydroxyhydantoin
NH
N
trans-1-carbamoyl-2-oxo-4,5- dihydroxyimidazolidine
NH
HN
OCHO
5-formyluracil
H
OH
O
O
CH
H
H
H OOCH
O
CH
OH
NH2
H
OH
H
O
O H
OH
H
O H
H
H
OH
NH2
O H
NH2
OHH
O H
O
OH
O H
OH
O
O
OH
NH2
OH
O
OH
OH
H
HO
H
OO OH
O
NH2
OH
NH2
H
NH2
H2NOHH
O O
H2N
O
H
H
OH
O
O
O
CH3
OH
O OH
HH
OHCO
NH2
HO
NH
N
N
O
NH2N
O
HOH
HHH
C
H
H
HO
(5'S)-8,5'-cyclo-2'-deoxyguanosine
NH
N
N
O
NH2N
O
HOH
HHH
C
H
HO
H
(5'R)-8,5'-cyclo-2'-deoxyguanosine
N
N
N
N
O
HOH
HHH
C
H
H
HO
(5'R)-8,5'-cyclo-2'-deoxyadenosine
NH2
N
N
N
N
O
HOH
HHH
C
H
HO
H
(5'S)-8,5'-cyclo-2'-deoxyadenosine
NH2
Reviewed in:Evans, M. D., Dizdaroglu, M. and Cooke, M. S., Mutat. Res. 567, 1-61, 2004
Consequencias moleculares de lesoes no DNA:
1. Mutagenese:
2. Citotoxicidade:
Polimerases especiais evoluiram para “bypass” lesions bloqueadoras
MAMMALIAN DNA REPAIRNuclear
Mitochondrial
DNA repair pathways
Base Excision RecombinationPostreplication Mismatch Nucleotide
ExcisionDirect
Reversal
Short Patch Long Patch TCR Gene Global
TCR
DNA Repair Pathways
Base ExcisionRecombinationPostreplication
??
Mismatch??
NucleotideExcision
Probably notDirect
Reversal
Short Patch
Xeroderma Pigmentosum e a descoberta de reparo de excisão
A Sindrome de Cockayne e o reparo acoplado a transcição
A via de “Nucleotide Excision Repair (NER)”
DAMAGED BASE
Glycosylase
5’ 3’
DNA ligase IIIXRCCI
Polβ
DNA ligase IIIXRCCI
APendo + Polβ APlyase
APendo + Polδ/ε
A B
DNA ligase I
FEN1/PCNA
Polδ,β/PCNA
APendo
C
Base excision repair
A via de “mismatch repair”
MMR em eucariotos é bastante similar a via procariótica
O reparo de quebras de fita dupla de DNA pode usar duas vias:
1. Via recombinacional (fiel)
2. Via nao-homologa (mutagenica)
O reparo de “cross-links” utiliza componentes de varias vias de reparo:
Lesoes no DNA ativam uma robusta resposta de sinalizacao celular
•Cancer
•Sindromes de fotosensibilidade
•Sindromes de envelhecimento precoce
•Neurodegeneracao
•Sindromes imunes e inflamatorias
•Envelhecimento normal
