分子生物学分子生物学 (11).pdf

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1、Chapter 6Mechanisms of DNA Damage and Repair6.1 Causes and Consequences of DNA Damage1Frequency of DNA damage in mammalian cellsTypes of DNA damageTimes Cell-1 Day 1DNA single strand break55 000Depurination10 000Depyrimidine200O6methylguanine3 100Cytosine deamination200Thymine glycol270Thymidine gly

2、col70Causes of DNA DamageSpontaneousfactorsReplication errorBase shedding or partial sheddingReactive oxygen species UVIonizing radiationAlkylating agentsBase analogsBase modifying agentsDNAphysical factorschemical factors6.1.1 Spontaneous Damage to DNA Molecules(1)DNA Replication ErrorDNA polymeras

3、e ITemplateBasesExonuclease hydrolysisThymine and guanine have ketoand enol tautomers.Cytosine and adenine have amino or imino tautomers.Under normal physiological conditions,the base interconversion equilibrium reaction tends to be keto or amino.(2)Spontaneous chemical changes of DNATautomerization

4、 of BasesThymine(T)Cytosine(C)Guanine(G)Adenine(A)Common keto or aminoRare enol or iminoA-TC-GA-CT-GRare formCommon formThymine(T)Thymine(T)Guanine(G)Guanine(G)Cytosine(C)Cytosine(C)Adenine(A)Adenine(A)Common formRare formDeamination of BasesDepurination and DepyrimidineBase Modification and Strand

5、BreakThe reactive oxygen species produced by cells in normal physiological activities can cause DNA damage,such as thymine glycol,hydroxymethyluraciland strand break.Loop Out Effect6.1.2 DNA damage caused by physical factors(1)DNA Damage Caused by Ultraviolet RadiationAdjacent pyrimidines on the sam

6、e DNA strand are covalently linked to form a dimer(T-T,C-T,C-C),which makes replication impossible.The frequency of dimer formation due to ultraviolet radiation can reach 5104/cell per hour in skin.Ultraviolet radiation can also cause DNA strand breaks.(2)DNA Damage Caused by Ionizing RadiationDirec

7、t effect:DNA absorbs radiation energy and is damaged.Indirect effects:Other molecules around the DNA(mainly water molecules)absorb the radiation energy and generate free radicals which damage the DNA.Types of DNA damage caused by ionizing radiation1)Base changes2)Deoxyribose decomposition3)DNA stran

8、d break4)Cross-linking6.1.3 DNA Damage Caused by Chemical Factors(1)DNA damage caused by alkylating agents1)Base alkylation2)Base shedding3)DNA strand break4)Cross-linking 5-BrdU （5-BrdU-A；5-BrdU-G）keto enol(2)DNA damage caused by base analogsand base modifying agents Nitrosamine (CU)Hydroxylamine(T

9、C)Aflatoxin B1 (GT)Repairable damageCauses of DNA damagephysical factorschemical factorsDegree of damageIrreversible damageCellular responseCell Fate cell survivalcell deathSpontaneous factorsDNA damage18Activate Survival Response NetworkCell cycle arrest and DNA repairMutations,chromosomal aberrationsActivate apoptosis pathwayCell malignant transformationBifunctional alkylating agentThank You!Thank You!