UVA UVB UVC 320 400 nm 290 320

Фотореактивация UV-A UV-B UV-C (320– 400 nm) (290– 320 nm) (100– 290 nm) 6

8

Direct repair by photoreactivation. 14

PLAY 17

Mismatch repair (MMR)

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If the tautomeric shift is slow, DNA polymerase moves on and a mismatch is incorporated into the DNA 22

Deamination of Cytosine creates a G-U mismatch Easy to tell that U is wrong Deamination of 5 -methyl cytosine creates a G-T mismatch Not easy to tell which base is the mutation. В 50% случаев G “исправляется” на A, что приводит к мутации 23

A closer look at mismatch repair 26

Mismatch mechanism PLAY

Гомологи генов Mut. S, Mut. L у эукариот E. coli S. cerevisiae S. pombe C. elegans D. melanogast er A. Thaliana Human Mut. S MSH 2 MSH 3 MSH 6 - MSH 2 SWI 4 MSH 6 - MSH 2 MSH 6 - SPEL 1 MSH 6 - MSH 2 MSH 3 MSH 6 MSH 7 MSH 2 MSH 3 MSH 6 - Mut. L MLH 1 PMS 1 MLH 2 MLH 3 - Mut. H Гомологов у эукариот нет Возникли за счет эндосимбио тических событий EXO 1 MLH 1 PMS 1 - - MLH 1 PMS 2 - TOSCA MLH 1 PMS 1 MLH 3 - Q 9 C 7 N 8 AAK 91436 MLH 1 PMS 2 MLH 3 PMS 1 EXO 1 28

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Base excision repair

Repairing apurinic and apyrimidinic sites

Nucleotide excision repair

Mechanism of Incision by the NER Pathway E. coli 5’ incision is 8 nuc. from lesion 3’ incision is 4 nuc. from lesion Mammals 5’ incision is 22 nuc. from lesion 3’ incision is 6 nuc. from lesion PLAY 37

Genetics of NER in Humans Xeroderma Pigmentosum (classical) • Occurrence: 1 -4 per million population • Sensitivity: ultraviolet radiation (sunlight) • Disorder: multiple skin disorders; malignancies of the skin; neurological and ocular abnormalities • Biochemical: defect in early step of NER • Genetic: autosomal recessive, seven genes (A-G) Xeroderma Pigmentosum (variant) • Occurrence: same as classical • Sensitivity: same as classical • Disorder: same as classical • Biochemical: defect in translesion bypass 38

Xeroderma Pigmentosum 39

Genetics of NER in Humans Cockayne’s Syndrome • Occurrence: 1 per million population • Sensitivity: ultraviolet radiation (sunlight) • Disorder: arrested development, mental retardation, dwarfism, deafness, optic atrophy, intracranial calcifications; (no increased risk of cancer) • Biochemical: defect in NER • Genetic: autosomal recessive, five genes (A, B and XPB, D & G) 40

Cockayne’s Syndrome 41

Genetics of NER in Humans Trichothiodystrophy • Occurrence: 1 -2 per million population • Sensitivity: ultraviolet radiation (sunlight) in subset of patients • Disorder: sulfur deficient brittle hair, mental and growth retardation, peculiar face with receding chin, ichthyosis; (no increased cancer risk) • Biochemical: defect in NER • Genetic: autosomal recessive, three genes (TTDA, XPB, XPD) 42

Trichothiodystrophy 43

SOS system

SOS system