dna损伤与修复的分子基础课件

1、DNA damage and repairJun Mei (糜军), MD & Ph.DDepart. of Biochemistry and Molecular Cell Biology, Shanghai Jiao-Tong University School of MedicineDNA damage and repairJun Mei (DNA（脱氧核糖核酸）Adenine Thymine Guanine Cytosine12345+糖苷键戊糖DNA（脱氧核糖核酸）Adenine Base pair氢键Base pair氢键Location of DNANuclear DNA Chro

2、matin/ChromosomeMitochondrial DNA Histone?Location of DNANuclear DNAThe cause of DNA damageThe pattern of DNA damageDNA damageThe cause of DNA damageDNA damThe cause of DNA damageDirect Radiation, UV, Chemical exposure Indirect Cellular metabolism, replication errorThe cause of DNA damageDirectThe p

3、attern of DNA damageOxidationAlkylation (methylation)HydrolysisBulky adduct formationMismatchThe pattern of DNA damageOxidaDirect cause of DNA damagePyrimidine dimer OxidationDirect cause of DNA damagePyriCytosine Methylated cytosineCytosine methylationCytosine MethylIndirect cause of DNA damageIndi

4、rect cause of DNA damageCellular response to DNA damageCellular response to DNA damagDNA RepairDNA RepairDirect reversal repairMGMT, methyl guanine methyl transferaseDirect reversal repairMGMT, meBase excision repairBase excision repairProkaryotes UvrA, UvrB, UvrC, DNA helicase IIEukaryotes XPA, XPB

5、, XPC, XPD, XPE, XPF, XPG, CSA, CSB, ERCC1, RPA, Rad23 Transcription-coupled NER: CSA/CSB Global genomic NER: XPC/Rad23BNucleotide excision repairProkaryotesNucleotide excisionMismatch repairMismatch repairDouble-strand Breaks RepairHomologous Recombinant DSBA, SDSA, SSA, BIRNon-Homologous End-joint

6、Double-strand Breaks RepairHomHomologous RecombinantHolliday JunctionMeiosisDNA damageHomologous RecombinantHollidaySSA: Single strand annealingDSB occurred between two repeat sequencesResults in deletions of genetic materialBIR: Break-induced replicationDSB happened at the replication Forkmechanism

7、 is unclearSSA: Single strand annealingBIEnzymes involved HREnzymes involved HRNon-Homologous End-joiningNon-Homologous End-joiningDetermination of cellular response to DNA damageDetermination of cellular respDNA damage signaling pathway(9-1-1 complex)ATM, ATR, DNA-PKDNA damage signaling pathway(9Ce

8、ll cycle regulation in Response to DNA damageCell cycle regulation in RespoATM pathwayATM pathwayThe difference of ATR and ATMThe difference of ATR and ATMDNA-PK pathwayDNA-PK pathwayPIP2PIP3PI3KPTENINPP4BFunction of PI3KAktPIP2PIP3PI3KPTENFunction of PIPI-3K kinase pathwaysPI-3K kinase pathwaysPhys

9、iological regulation of DNA repairKey factors:NutritionAgingNeuroendocrine(Sleeping)Physiological regulation of DNRecommended 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;99:33-58ATR: an essential regulator of genome integrity. Nature reviews Molecular Cell Bio