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DNA Repair Types

DNA Repair Types. Direct repair Alkylguanine transferase Photolyase Excision repair Base excision repair Nucleotide excision repair Mismatch repair Recombination repair. Direct repair: O 6 -alkylguanine DNA alkyltransferase (AGT).

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DNA Repair Types

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  1. DNA Repair Types • Direct repair • Alkylguanine transferase • Photolyase • Excision repair • Base excision repair • Nucleotide excision repair • Mismatch repair • Recombination repair

  2. Direct repair: O6-alkylguanine DNA alkyltransferase (AGT) • Directly repaires O6-alkylguanines(e.g. O6-Me-dG, O6-Bz-dG) • In a stoichiometric reaction, the O6 alkyl group is transferred to a Cys residue in the active site. The protein is inactivated and degraded.

  3. AGT inhibitor O6-benzylguanine is in clinical trials to be used in conjunction with antitumor alkylnitrosoureas

  4. AGT overexpression in tumors makes them resistant to alkylnitrosoureas

  5. Combination therapy with O6-benzylguanine overcomes tumor resistance to alkylnitrosoureas

  6. Excision Repair • Takes advantage of the double-stranded (double information) nature of the DNA molecule. • Four major steps: • Recognize damage. • Remove damage by excising part of one DNA strand. • The resulting gap is filled using the intact strand as the template. • Ligate the nick.

  7. Antiparallel DNA Strands contain the same genetic information 5' 5' 5' 3' 3' 3' A :: T A :: T A :: T G ::: C G ::: C G T :: A T :: A T :: A 5' 5' 5' 3' 3' 3' Original DNA duplex DNA duplex with one of the nucleotides removed Repaired DNA duplex

  8. X a n t h i n e Base excision repair (BER) • Used for repair of small damaged bases in DNA (AP sites, methylated bases, deaminated bases, oxidized bases…) • Human BER gene hogg1 is frequently deleted in lung cancer O N N H N N O H

  9. Uracil DNA glycosylase removes deaminated C No Me group N H O 2 BER C N N H N O N O Cytosine Not normally present in DNA U r a c i l Normal DNA base Not recognized by BER

  10. Nucleotide Excision Repair • Corrects any damage that both distorts the DNA molecule and • alters the chemistry of the DNA molecule (pyrimidine dimers, • benzo[a]pyrene-dG adducts, cisplatin-DNA cross-links). • Xeroderma pigmentosum is a genetic disorder resulting • in defective NER

  11. Mismatch Repair Enzymes • Nucleotide mismatches can be corrected after DNA synthesis! • Repair of nucleotide mismatches: • Recognize parental DNA strand (correct base) and daughter • strand (incorrectbase) • Parental strand is methylated: • 2. Replace a portion of the strand containing erroneous nucleotide • (between the mismatch and a nearby methylated site –up to 1000 nt) G T

  12. Genetic diseases associated with defective DNA repair Xeroderma Pigmentosum NER Hereditary nonpolyposis MMR colorectal cancer Cockrayne’s syndrome NER Falconi’s anemia DNA ligase Bloom’s syndrome BER, ligase Lung cancer (?) BER

  13. Chapter 3. RNA synthesis (Transcription) Required reading: Stryer 5th edition p. 129-132, 781-792 (or Stryer 4th edition p. 95-102, 841-849, 851-859)

  14. Flow of genetic information DNA RNA Proteins Cellular Action replication transcription translation DNA

  15. C U G U G G•C A•U C•G C•G G•C C•G C•G G•C 5'-U•C•C•C•A•C A•U•U•U-3' RNA is a biopolymer consisting of ribonucleotide units 5’ RNA is usually single stranded but can form hairpin structures by folding over the same strand: Loop Double- stranded region (stem) 3’

  16. Structural differences between DNA and RNA DNA RNA

  17. RNA Types • mRNA = Messenger RNA; an RNA copy of the DNA sequence (gene) used as a template for protein synthesis • tRNA = Transfer RNA; a small RNA that is attached to an amino acid which can be added to a growing peptide chain • rRNA = Ribosomal RNA; component of ribosomes with catalytic and structural function • snRNA = Small nuclear RNA, involved in RNA splicing in • eukaryotes

  18. RNA in E. coli

  19. 2Pi RNA synthesis • RNA synthesis involves transcribing a specific portion of DNA strand • into RNA sequence • RNA polymerases sequentially add ribonucleotides to the 3’ end • of an RNA polymer using DNA strand as a template (5’  3’ direction) • RNA Pol selects ribonucleotides complementary to the DNA • template and catalyzes the formation of new phosphodiester bonds. • This process is repeated as the enzyme moves along the DNA.

  20. RNA Synthesis: addition of new NTPsfollows Watson-Crick rules H N 2 NH 2 NH 2 N O N O N NH N N N HN N N N N O O A•U G•C Template base Incoming base G C C G U A A U

  21. Coding strand 5’…A T G G C C T G G A C T T C A…3’ 3’…T A C C G G A C C T G AA G T…5’ 5’- A U G G C C U G G A C U U C A…3’ Transcription Non-coding (template) strand Translation …Met-Ala-Trp-Thr-Ser… Peptide The sequence of the RNA transcript is complementary to the transcribed DNA strand and is the same as the coding strand

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