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DNA Repair and Recombination

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DNA Repair and Recombination DNA Repair and Recombination Metabolism, radiation, environmental substances… Liuh-yow Chen Molecular Biology of the Cell, Chapter 5 Outline 1. DNA damages and mutations 2. Base Excision Repair (BER), Nucleotide Excision Repair (NER), Mismatch Repair (MMR), etc. 3. Double-strand breaks repair: Nonhomologous End Joining (NHEJ) & Homologous Recombination (HR) 4. HR for meiosis Spontaneous Alterations of DNA Hydrolysis Oxidation Methylation A/G T/C Depurination and Deamination DNA lesions disrupt base pairing UV induces Pyrimidine Dimer UV light triggers a oxidation reaction to generate a covalent linkage between two neighboring pyrimidines Cyclobutane Pyrimidine dimers: TT, CC, CT, TC Pyrimidine dimer disrupts base pairing Damages to Mutations -> Mutations Damages-> Disrupted base pairing -> Repaired Base Excision Repair (BER) • Base Damages, Single Strand Breaks (ROS attacks). Recognition & cut AP site: apurinic/ apyrimidinic Glycosylases , xanthine DNA methylation for gene inactivation Cytosine methylation-- deamination--Thymine C:G>T:G mispair Thymine DNA glycosylase (TDG), methyl-CpG-binding protein 4 (MBD4) Nucleotide Excision Repair (NER) *Bulky lesions, UV, Tobacco smoke… DNA adducts ERCC1/XPF * Recognition ? UV-DDB, RPA, XPD.. ~ 30 nt humans Mismatch Repair (MMR) Mismatches: base-base mismatches, insertion/deletion loops (IDLs) Recognition: MSH2/MSH6, MSH2/MSH3 Strand discrimination:MLH1/PMS2, MLH1/PMS1 Translesion Synthesis (TLS) • TLS is used upon heavy damages (pyrimidine dimers) with DNA PCNA Ubiquitination replication. • Translesion polymerases (TLS) are less discriminating in choosing nucleotide for synthesis and lack exonuclease activity. > Error prone Double Strand Break (DSB) p The most deleterious form of DNA damage p Generated by IR radiation, free radicals, topoisomerase II inhibitor, VDJ recombination, meiotic recombination etc p Repaired by two major pathways: Homologous recombination (HR) Nonhomologous end-joining (NHEJ) Double-Strand Break Repair (G1/S/G2) (S/G2) Error-prone Error-free NHEJ Ku70/Ku80 DNA-PKc Artemis nuclease XRCC4/Ligase IV HR * After DNA replication (S/G2) * DSB recognition by MRE11/RAD50/NBS1 * End processing and resection: CtIP, MRE11/RAD50/NBS1, ExoI * RecA/Rad51 mediate strand invasion RecA/Rad51 for Strand Invasion /Rad51 RPA BRCA2 Helical nucleoprotein filament Rad52, Rad54 Homology searching HR Rescues Broken DNA Replication Forks DDR Activates Cell Cycle Checkpoints G1 check point: Preventing DNA synthesis that allows damages to become mutations. S phase delay: Decreasing the rate of DNA synthesis G2 check point: Preventing division of the cells with damages (chromosome breakage, loss). Diseases Due to Defects in DNA Repair HR for Genetic Recombination during Meiosis Germ cell Genetic Recombination: Homologous pairing Generation of a novel set Synapsis of genetic information that can be passed on from the parents to the offspring. Meiosis I HR / crossing over Meiosis II Gametes Crossover and gene conversion Genetic recombination = Gene conversion+ Chromosomal crossover HR in meiosis Spo11- Meiosis specific endonuclease Rad51 HR in meiosis A B a b A b a B Heteroduplex Holliday Junctions * Holliday junction is a branched nucleic acid structure that contains four double-stranded arms joined together. * Intermediate in meiosis. * Isomerization: Structural transformation. * Branch Migration: Breaking and re-forming of base pairs (ATP hydrolysis) Heteroduplexes formed by HR HR Results in Gene Conversion !! HR results in genetic recombination (mutations) in meiosis !! !!! HR for DSB does not lead to gene conversion!!! Abstract | Mitochondrial DNA (mtDNA) faces the universal challenges of genome maintenance: the accurate replication, transmission and preservation of its integrity throughout the life of the organism. Although mtDNA was originally thought to lack DNA repair activity, four decades of research on mitochondria have revealed multiple mtDNA repair pathways, including base excision repair, single-strand break repair, mismatch repair and possibly homologous recombination. These mtDNA repair pathways are mediated by enzymes that are similar in activity to those operating in the nucleus, and in all cases identified so far in mammals, they are encoded by nuclear genes..
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