biology

depurination & deamination

-> bc of reactive metabolites produced in the cell or chemical exposure from environment

• Direct Reversal (Direct Repair)

• Base excision repair (BER)

• DNA Mismatch repair (MMR)

• Nucleotide excision repair (NER)

• DNA strand break repair pathways

  • Single strand break repair (SSBR)

  • Double-strand break repair pathways (DSBR)

    • Homologous Recombination (HR)

    • Nonhomologous end joining

• “undo button”

• toxic chemical puts “methyl tag” on DNA bases (esp. guanine) -> not wanted -> enzyme MGMT takes this tag onto itself -> gets inactivated (one-time-use superhero)

• “little precise erasor”

• only bases got damaged (bc of reactive oxygen species, alkylation, deamination, x-rays) or lost

• identified by Glucosylase

• removed by Endonucleases

• replaced by DNA Polymerase & DNA Ligase

• “spellchecker”

• Detection

  • MSH2/MSH6 (MutS-a) -> mispaired bases , IDL (insertions-deletion loops)

  • MSH2/MSH3 (MutS-b) -> IDL

• strand removed by MLH1/PMS2 (exonuclease)

• replaced by DNA Polymerase & DNA Ligase

mutation of genes MLH1 or MSH2 -> Lynch syndrome -> increased risk of colon cancer

• “construction crew”

• UV caused 2 bases (esp. thymine) to stick together -> cuts out whole piece and rebuilds with new bricks

• Detection of ds helix distortion

  • by Global-NER (damage throughout genome)

  • by Transcription-coupled- NER (damage in transcriptionally active genes)

• DNA Helicase (open DNA around damage) -> Excision nuclease (cut out section) -> DNA Polymerase & DNA Ligase (repair)

mutation of XPA or XP genes -> Xeroderma Pigmentosum -> increased risk of skin cancer, sensitive to sunlight

BER (Base exicision repair) NER (Nucleotide exicison repair)

• BER: individual base; NER: dimer

• BER: 1 base removed by Endonuclease; NER: segment cut out via Excision Nuclease & DNA Helicase

• BER: 1 base replaced & ligased, NER: whole segment rebuilt

TLS (Translesion synthesis) by Special Translesion DNA Polymerase -> DNA damage tolerance process

• phosphorylation of PI3K-related kinase

  • DNA-PKcs, ATM or ATR

    -> phosphorylate other pr

    • CHK1 or CHK2 -> checkpoint kinases in cell cyle (“red light”)

    • p53 -> stop cell cycle or induce apoptosis

• detected by PARP (Poly-ADP Ribose)

• repaired by XRCC1, DNA Ligase III, DNA Polymerase beta, EDP (End damage processing) enzymes f.e. APE, PNK, Aprataxin

• Non-homologous end joining (NHEJ)

  • “duct tape”

  • sticks broken ends together even if bases missing

  • Ku70/80, DNA-PKcs, Artemis, XRCC4, Ligase IV, XLF

• Homologous recombination (HR)

  • “blueprint fix”

  • waits for sister chromatid during cell division and creates identical copy to patch the break

  • MRN complex, RPA, RAD51 & 52, BRCA1 & 2

BRCA1 & 2

(2 also prostate cancer)

• Ataxia-telangiectasia

  • autosomal recessive

  • neurodegeneration, ataxia, lymphoma, radiation sensitivity

• higher XPA expression at 5pm than 5am -> irritation with UVB at 5am -> higher risk of skin carcinoma

mtDNA repair systems can repair ss & ds DNA breaks

• change in gene dosage (genetic imbalance of entire chromosome or chromosomal regions)

  1. abnormal chromosome segregation (nondisjunction)

  2. recurrent chromosomal syndromes (deletions or duplications at genomic hot spots on chromosomes in many people)

  3. idiopathic chromosomal abnormalities (sporadic/de novo; not inherited)

  4. unbalanced familial chromosomal abnormalities (one parent with balanced translocation, child inherits unbalanced chromosome)

  5. genomic imprinting (one gene, maternal or paternal, naturally switched off -> other one maybe missing or not functioning)

the smaller the gene number (& also chr. size) of the chromosome involved in the aneuploidy, the better chance of the human to survive (f.e. trisomy 13, 18, 21 -> 21 only one seen in adults; monosomy sex chr.)

-> if high gene number not able to survive therefore not seen in population

• monosomy (one chr missing from a pair)

• disomy (normal unless:)

  • heterodisomy (2 different chr from one parent)

  • isodisomy (2 identical chr from one parent)

  • least common nondisjunction

• trisomy (extra chr in one pair)

Trisomy rescue (“fix” when there is an extra copy of a chr in apair)

Down syndrome (Trisomy 21)

95% extra copy of chr.21

2% mosaic patients (only some cells extra copy)

• 2 acrocentric chromosomes stick together at centromere -> 1 big chr. (usually 13, 14, 15, 21 or 22) -> 45 instead of 46 chr. but all genetic material (balanced)

• person healthy but children affected bc unbalanced (f.e. translocation Down syndrome)

• 21q21q Translocation

  only a part of the long arm of chr. 21 is present in triplicate

• heart defect in 40% Down syndrome patients