Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10915288 | Mutation Research/Reviews in Mutation Research | 2012 | 89 Pages |
Abstract
The faithful maintenance of chromosome continuity in human cells during DNA replication and repair is critical for preventing the conversion of normal diploid cells to an oncogenic state. The evolution of higher eukaryotic cells endowed them with a large genetic investment in the molecular machinery that ensures chromosome stability. In mammalian and other vertebrate cells, the elimination of double-strand breaks with minimal nucleotide sequence change involves the spatiotemporal orchestration of a seemingly endless number of proteins ranging in their action from the nucleotide level to nucleosome organization and chromosome architecture. DNA DSBs trigger a myriad of post-translational modifications that alter catalytic activities and the specificity of protein interactions: phosphorylation, acetylation, methylation, ubiquitylation, and SUMOylation, followed by the reversal of these changes as repair is completed. “Superfluous” protein recruitment to damage sites, functional redundancy, and alternative pathways ensure that DSB repair is extremely efficient, both quantitatively and qualitatively. This review strives to integrate the information about the molecular mechanisms of DSB repair that has emerged over the last two decades with a focus on DSBs produced by the prototype agent ionizing radiation (IR). The exponential growth of molecular studies, heavily driven by RNA knockdown technology, now reveals an outline of how many key protein players in genome stability and cancer biology perform their interwoven tasks, e.g. ATM, ATR, DNA-PK, Chk1, Chk2, PARP1/2/3, 53BP1, BRCA1, BRCA2, BLM, RAD51, and the MRE11-RAD50-NBS1 complex. Thus, the nature of the intricate coordination of repair processes with cell cycle progression is becoming apparent. This review also links molecular abnormalities to cellular pathology as much a possible and provides a framework of temporal relationships.
Keywords
DSBHRRdsDNAATRMMCPCCMOFMEFGFPeGFPFRAPNHEJBRCBRMBAFBLMP300CBPBcl2PARPATF2MRNBrg1dNTPDNMT3BCHFRPHF1DNA methyltransferase 3Bp14ARFPHDBARD1BCCIPH2AXMus81Chk1a.a.CUL3FHALIG4Ataxia telangiectasiaHus1BRCTDNA-PKKBD53BP1DNA-PKcsMG1329–1–1MSLDUBNPM1NuA4GCN5HP1ISWIKAP1MMEJNuRDALC1MUM1FANCPIASE2F-1Fe65DSS1CtIPMRG15INO80Mms2AprataxinEsa1Eme1PCNAPFGEPolynucleotide kinase/phosphataseGEN1PNKPCHRACBmi1double-stranded DNAhTERTPIKKNAD+amino acidoligonucleotide/oligosaccharide bindingLETPulse field gel electrophoresisLinear Energy TransferATLDChoionizing radiationChinese Hamster OvaryPremature chromosome condensationHomologous recombination repairhuman telomerase reverse transcriptaseParD-loopdisplacement loopATMembryonic stemNijmegen breakage syndrome 1double-strand breakfluorescence recovery after photobleachingprotein inhibitor of activated Statmouse embryonic fibroblastNucleophosmin 1nicotinamide adenine dinucleotideHistone acetyltransferasePatmgreen fluorescent proteinenhanced green fluorescent proteinheterochromatin protein 1Poly(ADP-ribose)microhomology-mediated end joiningNonhomologous end joiningCHiPERCC1KRABChromatin Immuno-PrecipitationHATFanconi anemia
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Authors
Larry H. Thompson,