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DNA can become damaged through various sources such as UV radiation, chemical agents, and cellular metabolism. This document categorizes different types of DNA damage and the repair pathways that fix each type. It discusses several DNA repair mechanisms including base excision repair, mismatch repair, nucleotide excision repair, homologous recombination repair, and non-homologous end joining. Each repair pathway recognizes specific damaged bases or breaks and repairs the DNA accurately through different mechanisms such as excising the damaged area and using a complementary strand as a template for new DNA synthesis.
DNA can become damaged through various sources such as UV radiation, chemical agents, and cellular metabolism. This document categorizes different types of DNA damage and the repair pathways that fix each type. It discusses several DNA repair mechanisms including base excision repair, mismatch repair, nucleotide excision repair, homologous recombination repair, and non-homologous end joining. Each repair pathway recognizes specific damaged bases or breaks and repairs the DNA accurately through different mechanisms such as excising the damaged area and using a complementary strand as a template for new DNA synthesis.
DNA can become damaged through various sources such as UV radiation, chemical agents, and cellular metabolism. This document categorizes different types of DNA damage and the repair pathways that fix each type. It discusses several DNA repair mechanisms including base excision repair, mismatch repair, nucleotide excision repair, homologous recombination repair, and non-homologous end joining. Each repair pathway recognizes specific damaged bases or breaks and repairs the DNA accurately through different mechanisms such as excising the damaged area and using a complementary strand as a template for new DNA synthesis.
DNA repair acronyms (this page and next page) BER = Base excision repair MGMT = Methylguanine methyltransferase NHEJ = Non-homologous end joining HRR = Homologous recombination repair MMR = Mismatch repair TL Pol Translesion Pol zeta
Categorizing DNA Damage and correlating damage with its sources and potential DNA Repairs Damage Sources Repaired by: Helical distortion due to abnormal H-bonds between bases Mismatch Spontaneous: misincorporation during DNA Pol synthesis or tautomerized bases MMR ssDNA loops Spontaneous: DNA Pol slipping on repeated sequences MMR Deaminated bases (e.g., dU) Sponteneous hydrolysis due to cellular water Nitrates (preservatives in hot dogs, etc.) BER or MMR Abnormal single nucleotides due to addition of chemical groups Oxidized bases (e.g., T-OH) Spontaneous oxidation by reactive chemicals created by cellular metabolism Increased by infection that increases release of oxidizing compounds BER or MMR Alkylated bases (e.g., Me-G) Spontaneous alkylation by reactive chemicals created by cellular metabolism Chemotherapeutic alkylating agents strongly damage DNA by alkylation BER, MMR or MGMT Cross-linked nucleotides connected by abnormal covalent bonds Pyrimidine dimers UV radiation creates TT or TC pyrimidine dimers TC-NER or GG-NER Cisplatin Cisplatin chemotherapy cross-links purines (G) with platinum Recognized by MMR Broken phosphodiester backbone ssDNA breaks Ionizing radiation (x-rays, gamma rays) PARP with BER dsDNA breaks Replication across ssDNA breaks in template DNA strand; ionizing radiation (x-rays, gamma rays) causing such frequent ssDNA breaks that they break both strands in one region BRCA with HRR or NHEJ
2 Categorizing DNA Repair and correlating repairs with their target types of damage, accuracy and basic mechanism MGMT BER with glycosidases MMR
NER
BER with PARP HRR with BRCA NHEJ
Translesion Pol
What do the proteins of this repair/synthesis system recognize? (colors in this category correlate with Damage table on p. 1) Specific damaged nucleotides caused by: Minor* helical distortions due to: Major** helical distortions due to: DNA breaks:
Replication fork stalled by major helical distortion** Methylated G dU (de-aminated C) other oxidized, alkylated or de-aminated bases Mismatch ssDNA loop
Pyrimidine dimer Multiple oxidized or alkylated nucleotides ssDNA breaks dsDNA breaks dsDNA breaks Is original damage repaired accurately, repaired inaccurately or not repaired? Accurate Inaccurate: Not repaired; Direct repair: MGMT removes Me from G Excision repair uses nucleases to excise damaged nucleotides (if needed), complementary strand to direct accurate synthesis by Pol, and ligase to make final bond
Uses sister chromatid to direct repair Trims DNA ends deletion New strand syn- thesis continues inaccurately substitutions Glycosidase recognizes damaged base and cuts glycosidic bond to release it AP nuclease cuts sugar from backbone Pol replaces nucleotide Ligase makes final bond Recognition proteins bind to distortion and others scan for Me CpG to identify old strand***; Nucleases remove DNA back past distortion; Pol replaces DNA Ligase final bond
Also recognizes Cisplatin adducts not minor at all and initiates cell apoptosis (so MMR deficient cells are Cisplatin resistant) GG-NER: XP recog- nition proteins bind to distortion any- where in genome TC-NER: CSA/B proteins ride with Pol II and bind distor- tion that stalls Pol II For both: nucleases remove 12 nucleo- tides containing distortion Pol replaces DNA Ligase final bond ssDNA break recog- nition proteins bind PARP, which recruits BER nuclease, Pol and ligase to repair break. dsDNA break recognition proteins recruit BRCA, which recruits HRR proteins that use recombination mechanism to accurately repair dsDNA break NHEJ recognition proteins bind broken ends, recruit nucleases to trim them, then ligate them Stalled replica- tion fork can recruit TL Pol zeta to continue new strand synthesis past the distortion in template strand, but Pol zeta doesnt proof- read, so it introduces mismatches and substitution mutations *Helical distortions that wont stall a replication fork (DNA Polymerases) or RNA Pol II **Helical distortions severe enough to stall a replication fork (DNA Polymerases) or RNA Pol II ***MMR is only accurate during S phase before new strand has been methylated; otherwise MMR cant determine which strand has correct base.
2021-NC-Abraxas Suppresses DNA End Resection and Limits Break-Induced Replication by Controlling SLX4-MUS81 Chromatin Loading in Response To TOP1 Inhibitor-Induced DNA Damage