Process_DNARepair – DNA repair

Name
WID Process_DNARepair
Name DNA repair
 
Implementation
Initialization order 13 View in model
 
Reactions
Chemical reactions View in model
 
Parameters
Parameters View in model
 
Comments
Comments Introduction DNA can be damaged by many modes including hydrolysis, oxidation, and non-enzymatic methylation. The breadth and relative frequency of DNA damage modes was reviewed by Lindahl and Barnes [PUB_0462]. These damages are deleterious to many processes including transcription and replication, and thus are repaired by three pathways – base excision repair, nucleotide excision repair, and homologous recombination. Base excision repair is most closely associated with oxidative damage, and involves four steps: (1) 3' phosphodiester bond cleavage by a glycosylase, (2) 5' phosphodiester bond cleave by an AP endonuclease, (3) polymerization of a new base by DNA polymerase, and (4) ligation by DNA ligase. The nucleotide excision repair recognizes a wider range of DNA damage modes than base excision repair including damage caused by UV radiation and nitric oxide. Nucleotide excision repair involves five steps: (1) recognition of a segment of 12-13 nucleotides surrounding the damaged base by the UvrABC excinuclease, (2) cleavage of the 3' and 5' phosphodiester bonds of the damaged segment, (3) removal of the damage nucleotides by a 3'-5' helicase, (4) polymerization of new nucleotides by DNA polymerase, and (5) ligation by DNA ligase. Homologous recombination repairs double strand breaks caused by ionizing radiation and stalled replication forks. Homologous recombination occurs by three steps: (1) single-stranded binding (SSB) proteins binds single-stranded DNA, (2) SSBs recruit the protein recA which displaces the SSBs, and (3) RecA aligns homologous DNA strands, and executes strand exchange and migration with the RecU and RuvAB proteins. Each DNA damage mode is modeled as a Poisson process with a rate parameter equal to its experimentally measured rate. The three modes of DNA repair are modeled motivated by mass-action kinetics similar to RNA and protein maturation. Simulates repair of a spectrum of DNA lesions by the direct damage repair (DDR), base excision (BER), nucleotide excision (NER), and homologous recombination (HR) DNA repair pathways. The table below summarizes the pathways of DNA repair modelled here. Damage Repair Pathway Abasic site BER Damaged base BER, GG-NER Intrastrand crosslink GG-NER Single strand break DDR Double strand break HR-DSBR This module also simulates DNA damage recognition by the DNA integrity scanning protein DisA (MG_105). Direct Damage Reversal (DDR) The only direct damage repair homolog identified in M. genitalium is ligase ligA (MG_254). LigA is capable of repairing single strand breaks by a NAD-dependent mechanism: base O base O base O base O | || | || | || | || ...-O-sugar-O-P-O-sugar-O-P-O- + HO-sugar-O-P-O-sugar-O-P... + NAD | | | | O O O O || || V base O base O base O base O | || | || | || | || ...-O-sugar-O-P-O-sugar-O-P-O-sugar-O-P-O-sugar-O-P... + AMP + NMN + H | | | | O O O O Base Excision Repair (BER) Repairs specific spontaneously and endogenously produced DNA damaged including base modifications, abasic sites, and single strand breaks by the following mechanism [PUB_0084]: Base excision by Fpg (MG_498) or Ung (MG_097) glycosylase base O OH O | || | || -O-sugar-O-P... + H2O ==> -O-sugar-O-P + base | | O O 3'-AP lyase Fpg (MG_498) 5'-deoxyribosephosphodiesterase Nfo (MG_235) 5'-AP endonuclease Nfo (MG_235) 3'-(deoxyribose-5'-phosphate) lyase DnaN (MG_001) 5'-3' Polymerization by DnaN (MG_001) Ligation by LigA (MG_254). See DDR section for details. Catabolism and export of damaged nucleobases and nucleosides by metabolic module. Flap endonuclease fen1 homologs have not been identified in M. genitalium; MG_262 is a weak fen1 homolog, but is more strongly homologous to polI exonucleases. Consequently, we do not model flap base excision repair. Global Genomic (GGR) Nucleotide Excision Repair (NER) NER recognizes bulky distortions in the shape of the DNA helix caused by damaged bases and cross links [PUB_0084]. Consequently, NER has broader repair capability than base excision repair [PUB_0084]. Here we model only global genomic NER. In some bacteria such as E. coli DNA damage is sensed by RNA polymerase and coupled to the NER machinery by the transcription-repair coupling factor Mfd. UvrABC (MG_073, MG_206, MG_421) cleaves DNA 3' and 5' to lesion Helicase PcrA (MG_244) excises 12-13 bases between DNA cleavages [PUB_0084] Cleavage excised oligonucleotide by MgpA (MG_190) 5'-3' Polymerization by DnaN (MG_001) Ligation by LigA (MG_254). See DDR section for details. Catabolism and export of damaged nucleobases and nucleosides by metabolic module. Note steps (3) and (4-5) occur in parallel. Homologous Recombination (HR) Double Strand Break Repair (DSBR) Homologous recombination repairs double strand breaks caused by ionizing radiation, stalled replication forks, and β-elimination of abasic sites [PUB_0084]. M. genitalium has a very reduced complement of recombination repair proteins. Normally recombination repair involves the following steps [PUB_0084]: Initiation: 5'-3' exonuclease removes dNMPs from 5' ends of strands leaving 3' overhangs. Daley and Wilson have shown homologous recombination is most efficient with overhangs of at least 8 bases [PUB_0526]. No tradiational initiation gene has been identified in M. genitalium. 5'-3' resection could be carried out by PcrA (MG_244) or PolI-like (MG_262). Here we model PcrA as the NER helicase, and therefore choose to model PolI-like as the HR initiator. Strand exchange: One of the damaged 3' overhang invades the undamaged homologous chromosome, forming a holliday junction. Catalyzed by RecA (MG_339) 5'-3' Polymerization by DnaN (MG_001) 2 ligations by LigA (MG_254). See DDR section for details. Second strand exchange: The second damaged 3' overhang invades the undamaged homologous chromosome, forming a second holliday junction. Also catalyzed by RecA (MG_339) Holliday junction migration: RuvAB (MG_358, MG_359) widens distance between the two strand cross over points by moving holliday junctions to preferred sequence 5'-(A/T)TT?(G/C)-3' [PUB_0532]. Resolution: RecU (MG_352) dimer nicks DNA at cross over points creating four single strand breaks 4 ligations by LigA (MG_254). See DDR section for details. Catabolism and export of damaged nucleobases and nucleosides by metabolic module. DNA integrity scanning protein DisA In B. subtilis DisA recognizes strand breaks, base damage, and cross links (possibly through ssDNA, Holliday junctions, or stalled replication forks that are generated during recombination repair of these lesions), binds damaged DNA, and via an unknown mechanism delays sporulation. In addition DisA has diadenylate cyclization (produces c-di-AMP from 2 ATPs) activity which is abolished when bound to branched DNA such as Holliday junctions. c-di-AMP has been speculated as the second messenger which couples DisA damage recognition to regulation of the transcriptional regulator Spo0A, and delayed sporulation. The rest of the B. subtilis signaling system (spo0A, kinA, kinE) is not present in M. genitalium. DNA Restriction/Modification Organisms employ a restriction/modification systems to distinguish self from foreign DNA such as that of bacteriophages [PUB_0652, PUB_0653]. These systems methylate hemi-methylated DNA and cleave unmethylated DNA. The systems maintains self DNA in the fully methylated state so that it can be distinguished from foreign DNA (which will be unmethylated) on methylation status. M. genitalium contains a reduced restriction/modification system consisting of the EcoD type I DNA recognition subunit (MG_438) and the MunI type II methylatase (MG_184). M. genitalium does not contain a type III RM system. EcoD is the DNA binding (S) domain of a multimetric (M2R2S1) methylation and restriction complex. EcoD recognizes the sequence 5'-TCARTTC-3'. The other subunits (M) methylate the N(7) position of A-3, producing N(7)-methyladenine or (R) cleave DNA at this position. M. genitalium contains only the DNA recognition subunit. MunI methylase (MG_184) methylates the N(6) position of A-3 in the sequence 5'-CAATTG-3', producing N(6)-methyladenine. M. genitalium does not contain a MunI endonuclease. DNA repair mechanisms not present in M. genitalium Transcription-coupled NER (TC-NER) – M. genitalium does not have a transcription-repair coupling factor mfd homolog. Additional eukaryotic homologous recombination (HR) pathways Synthesis-dependent strand annealing (SDSA) Single-strand annealing (SSA) Break-induced replication (BIR) Non-homologous end joining (NHEJ) – M. genitalium does not have a dedicated NHEJ DNA ligase ligD or a DNA-end-binding protein Ku. Mismatch Repair SOS Response Metabolism of damaged nucleo-bases, -sides, and -tides No gene has been identified which cleaves DNA oligonucleotides; possible genes include pcrA (MG_244), mgpA (MG_190), and polI-like (MG_262). Here we model PcrA as the NER helicase and PolI-like as the HR resection enzyme, leaving MgpA without an assigned function. Therefore we choose to model MgpA as capable of cleaving oligonucleotides released by NER into single nucleotides. Nucleotides released by PolI-like or MgpA are returned to the cytoplasmic free pool, and are available to the metabolism module. Damaged nucleotides are degraded to nucleosides and are exported by the metabolism module. Damaged nucleobases are also exported by the metabolism module. References B.A. Sokhansanj, G.R. Rodrigue, J.P. Fitch and D.M. Wilson III (2002). A quantitative model of human DNA base excision repair: I. Mechanistic insights. Nuc Acids Res. 30(8): 1817-25. [PUB_0488] Sokhansanj BA, Wilson DM 3rd (2004). Oxidative DNA damage background estimated by a system model of base excision repair. Free Radic Biol Med. 37(3): 422-7. [PUB_0487] Politi A, Moné MJ, Houtsmuller AB, Hoogstraten D, Vermeulen W, Heinrich R, van Driel R (2005). Mathematical modeling of nucleotide excision repair reveals efficiency of sequential assembly strategies. Mol Cell. 19(5): 679-90. [PUB_0514] Alain Blanchard, Glenn Browning (2005). Mycoplasmas: molecular biology, pathogenicity and strategies for control. CRC Press. [PUB_0525] Carvalho FM, Fonseca MM, Batistuzzo De Medeiros S, Scortecci KC, Blaha CA, Agnez-Lima LF (2005). DNA repair in reduced genome: The Mycoplasma model. Gene. 360(2): 111-9. [PUB_0072] James M. Daley and Thomas E. Wilson (2005). Rejoining of DNA Double-Strand Breaks as a Function of Overhang Length. Mol Cell Biol. 25(3): 896-906. [PUB_0526]
References
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  4. Daley JM, Wilson TE. Rejoining of DNA double-strand breaks as a function of overhang length. Mol Cell Biol 25, 896-906 (2005). WholeCell: PUB_0526, PubMed: 15657419

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Metadata
Created 2012-10-01 15:07:35
Last updated 2012-10-01 15:13:59