dna損傷與修復的分子基礎38

1、DNA damage and repairJun Mei (糜軍), MD & Ph.DDepart. of Biochemistry and Molecular Cell Biology, Shanghai Jiao-Tong University School of MedicineDNA（脫氧核糖核酸）Adenine Thymine Guanine Cytosine12345+糖苷鍵戊糖Base pair氫鍵Location of DNANuclear DNA Chromatin/ChromosomeMitochondrial DNA Histone?The cause of DNA d

2、amageThe pattern of DNA damageDNA damageThe cause of DNA damageDirect Radiation, UV, Chemical exposure Indirect Cellular metabolism, replication errorThe pattern of DNA damageOxidationAlkylation (methylation)HydrolysisBulky adduct formationMismatchDirect cause of DNA damagePyrimidine dimer Oxidation

3、Cytosine Methylated cytosineCytosine methylationIndirect cause of DNA damageCellular response to DNA damageDNA RepairDirect reversal repairMGMT, methyl guanine methyl transferaseBase excision repairProkaryotes UvrA, UvrB, UvrC, DNA helicase IIEukaryotes XPA, XPB, XPC, XPD, XPE, XPF, XPG, CSA, CSB, E

4、RCC1, RPA, Rad23 Transcription-coupled NER: CSA/CSB Global genomic NER: XPC/Rad23BNucleotide excision repairMismatch repairDouble-strand Breaks RepairHomologous Recombinant DSBA, SDSA, SSA, BIRNon-Homologous End-jointHomologous RecombinantHolliday JunctionMeiosisDNA damageSSA: Single strand annealin

5、gDSB occurred between two repeat sequencesResults in deletions of genetic materialBIR: Break-induced replicationDSB happened at the replication Forkmechanism is unclearEnzymes involved HRNon-Homologous End-joiningDetermination of cellular response to DNA damageDNA damage signaling pathway(9-1-1 comp

6、lex)ATM, ATR, DNA-PKCell cycle regulation in Response to DNA damageATM pathwayThe difference of ATR and ATMDNA-PK pathwayPIP2PIP3PI3KPTENINPP4BFunction of PI3KAktPI-3K kinase pathwaysPhysiological regulation of DNA repairKey factors:NutritionAgingNeuroendocrine(Sleeping)Recommended ReadingATM and Related Protein Kinases: Safeguard Genome Integrity. Nature Reviews Cancer 2003;3;155-168Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nature reviews Molecular Cell Biology 2008;9:759-769DNA-PK The means to justify the Ends. Advances in Immunology 2008