武汉大学：《分子遗传学与现代遗传学》课程教学资源（高等遗传学，研究生）第9-10讲 DNA mutation, damage and repair

DNA mutation, damage and repair

DNA mutation, damage and repair

DNA修复与人类生活密切相关我喝的是酒流出的是血LiFeS....FocusOnLife生活焦点辐射无处不在的健康隐形杀手！中国NSEENE2E：ARISESSETETEECORXRECEESYOKAMEN.C长期吸烟和酗酒会导致DNA损伤，削弱和抑制身体DNA修复能力紫外线照射、辐射损伤DNA

DNA修复与人类生活密切相关 长期吸烟和酗酒会导致DNA损伤，削弱和抑制身体DNA修复能力； 紫外线照射、辐射损伤DNA

DNAmutationWhatisamutation?Substitution,deletion,orinsertionofa basepairChromosomaldeletion,insertion,orrearrangementSomatic mutations occurin somatic cells and onlyaffect the individual in whichthemutationarisesGerm-line mutations alter gametes and passed to the next generation

What is a mutation? • Substitution, deletion, or insertion of a base pair. • Chromosomal deletion, insertion, or rearrangement. Somatic mutations occur in somatic cells and only affect the individual in which the mutation arises. Germ-line mutations alter gametes and passed to the next generation. DNA mutation

TypesofbasepairsubstitutionsandmutationsSequence of mutated geneSequenceofpartofanormalgeneTransitionmutation(ATtoGCinthisexample)a)转换53'5'3TCTCAAAAATTTACGTCTCAAGAATTTACG3'535'AGAGTTTTTAAATGCAGAGTTCTTAAATGCb)Transversionmutation(CGtoGCinthisexample)颠换553'3'TCTCAAAAATTTACGTCTGAAAAATTTACG5'335'AGAGTTTTTAAATGCAGACTTTTTAAATGC错义突变c)Missensemutation(changefromoneaminoacidtoanother;hereatransitionmutationfromATtoGCchangesthecodonfromlysinetoglutamicacid)5'5'33'TCTCAAAAATTTACGTCTCAAGAATTTACG3'3'5°AGAGTTTTTAAATGC5LAGAGTTCTTAAATGCSerGin Lys PheThr-SerGIn GluPheThr:无义突变dyNonsensemutation(changefromanaminoacidto astopcodon;hereatransversionmutationfromATtoTAchangesthecodonfromlysinetoUAAstopcodon)5'5'3'3'TCTCAAAAATTTACGTCTCAATAATTTACG33'55AGAGTTTTTAAATGCAGAGTTATTAAATGC..Ser Gin Lys PheThr.....SerGin Stop

Types of base pair substitutions and mutations 错义突变 无义突变 转换 颠换

Sequence of partof a normal geneSequence ofmutated geneNeutral mutation(changefromanaminoacidtoanotheramino acidwithsimilare)中性突变chemicalproperties;hereanATtoGCtransitionmutationchangesthecodonfromlysineto arginine)35'5'3TCTCAAAAATTTACGTCTCAAAGATTTACG3'535AGAGTTTTTAAATGCAGAGTTTCTAAATGC.Ser Gln Lys PheThr...Ser GlnArgPheThr同义突变(synonymousmutation）Silentmutation (change in codon suchthatthe sameamino acidisspecified;hhereanAT-to-GCtransitioninthethirdpositionofthecodongivesacodonthatstillencodeslysine)3'5'3'5TCTCAAAAATTTACGTCTCAAAAGTTTACG53'5°3'AGAGTTTTTAAATGCAGAGTTTTCAAATGCSer Gin Lys Phe Thr...SerGlnLysPheThr-Frameshiftmutation(additionordeletionofoneorafewbasepairsleadstoag)changeinreadingframe:heretheinsertionofaGCbasepairscramblesthe移码突变messageafterglutamine)5'5'3'3TCTCAAAAATTTACGTCTCAAGAAATTTACG3'355AGAGTTTTTAAATGCAGAGTTCTTTAAATGC.Ser Gin Lys PheThr.....Ser GinGluIleTyr

同义突变（ synonymous mutation） 中性突变 移码突变

Spontaneousmutationsdifferfrom inducedmutations:Spontaneousmutationscanoccuratanypointofthecell cycleMovementoftransposons(mobilegeneticelements)Mutationrate=~10-4to10-6mutations/gene/generationRatesvarybylineage,andmostspontaneouserrorsarerepaired

Spontaneous mutations differ from induced mutations: • Spontaneous mutations can occur at any point of the cell cycle. • Movement of transposons (mobile genetic elements) • Mutation rate = ~10-4 to 10-6 mutations/gene/generation • Rates vary by lineage, and most spontaneous errors are repaired

SpontaneouschemicalchangescancausemutationExample:Deamination:C→U.C→Ta)NH2HDeaminationCytosineUracilb)MethylNH2groupCH3CH3DeaminationH5-methylcytosine (5mC)Thymine(T)

Spontaneous chemical changes can cause mutation Example : Deamination: C  U, C  T

Induced mutationsRadiation (e.g., X-rays, UV)lonizing radiation breaks covalent bonds including those in DNA and is the leadingcauseofchromosomemutationsUV (254-260 nm) causes purines and pyrimidines to form abnormal dimer bondsandbulgesintheDNAstrandsThymineThymineThyminedimer

Induced mutations Radiation (e.g., X-rays, UV) Ionizing radiation breaks covalent bonds including those in DNA and is the leading cause of chromosome mutations. UV (254-260 nm) causes purines and pyrimidines to form abnormal dimer bonds and bulges in the DNA strands. Thymine dimers induced by UV light

Inducedmutations:chemicalmutagensBaseanalogsSimilartonormal bases,incorporatedinto DNAduringreplicationSome cause mis-pairing (e.g., 5-bromouracil)Base modifying agents,actatanystage of thecell cycle:Deaminating agentsHydroxylatingagentsAlkylatingagents

Induced mutations: chemical mutagens Base analogs • Similar to normal bases, incorporated into DNA during replication. • Some cause mis-pairing (e.g., 5-bromouracil). Base modifying agents, act at any stage of the cell cycle: • Deaminating agents • Hydroxylating agents • Alkylating agents

突变发生在基因的非编码区调节位点ACAGCGTGGT在非编码区的点突变GAGCGTGGT调节蛋白不能结合调节区和非编码区的DNA序列DNA水平：包括RNA聚合酶、特定转录因子的结合位点；RNA水平：包括核糖体结合位点，真核生物mRNA外显子交接区5'和3端拼接位点，以及调节mRNA进入细胞特定区域和组分的翻译调节和定位信号位点

突变发生在基因的非编码区 调节区和非编码区的DNA序列: DNA水平: 包括RNA聚合酶、特定转录因子的结合位点； RNA水平：包括核糖体结合位点，真核生物mRNA 外显子交接区5′和3′端拼接位点, 以及调节mRNA进入细胞特定区域和组分的翻译调节和定位信号位点