麻省理工学院：《动物遗传学 Genetics》课程教学资源（英文讲义）Lecture 35 Alterations in different kinds of Genes cause Cancer

Genetics of Cancer Lecture 35

Genetics of Cancer Lecture 35

Alterations in different kinds of Genes cause Cancer Oncogenes dominant gain-of-function mutations promote cell transformation Tumor suppressor genes recessive,loss-of-function mutations promote cell transformation Mutator genes Usually recessive,loss-of-function mutations that increase spontaneous and environmentally induced mutation rates

Alterations in different kinds of Genes cause Cancer Oncogenes dominant gain-of-function mutations promote cell transformation Tumor suppressor genes recessive, loss-of-function mutations promote cell transformation Mutator genes Usually recessive, loss-of-function mutations that increase spontaneous and environmentally induced mutation rates

What chromosomal events convert proto- oncogenes to dominantly acting oncogenes Point mutations (e.g.,RAS) Partial deletion mutations (e.g.,RTKs) .Chromosomal translocations that produce novel fusion proteins (e.g.,Bcr-Abl) Chromosomal translocation to juxtapose a strong promoter upstream and the proto- oncogene such that it is inappropriately expressed (e.g.,cMyc,Bcl2) Gene amplification resulting in overexpression (e.g.,N-Myc)

What chromosomal events convert proto￾oncogenes to dominantly acting oncogenes • Point mutations (e.g., RAS) • Partial deletion mutations (e.g., RTKs) •Chromosomal translocations that produce novel fusion proteins (e.g., Bcr-Abl) • Chromosomal translocation to juxtapose a strong promoter upstream and the proto￾oncogene such that it is inappropriately expressed (e.g., cMyc, Bcl2) • Gene amplification resulting in overexpression (e.g., N-Myc)

Point Mutation Non-Dis junction LOH Loss of heterozygosity Chromosome Chromosome loss loss duplication wt l Rb Mutant Rb Recombination Interchromosomal Deletion Translocation Gene Conversion Recombination

Point Mutation Non-Disjunction Chromosome loss & duplication Chromosome loss Recombination Deletion Interchromosomal Recombination Translocation Gene Conversion wt Rb Mutant Rb LOH - Loss of heterozygosity

Sunlight Oxidation Pollution Food Cigarette Smoke Courtesy of Professor Bevin P.Engelward.Used with permission

Sunlight Pollution Oxidation Food Cigarette Smoke Courtesy of Professor Bevin P. Engelward. Used with permission

Excision Repair Proteins Detect Damage Enzymes Excise DNA Segment with Damage DNA Polymerase Copies the Undamaged Strand DNA Ligase Seals the ends together Courtesy of Professor Bevin P.Engelward.Used with permission

Excision Repair Proteins Detect Damage Enzymes Excise DNA Segment with Damage DNA Polymerase Copies the Undamaged Strand DNA Ligase Seals the ends together Courtesy of Professor Bevin P. Engelward. Used with permission

0 Deoxyribose-N C=0 0 CH3 H -N Deoxyribose-N C=0 H CH3 Two thymine residue UV irradiation 0 c一N Deoxyribose-N H C=0 CH3 ⊙ 0 -N Deoxyribose—N CC=0 H CH3 Thymine-thymine dimer residue Before After Figure by MIT OCW

Figure by MIT OCW

Sunlight Oxidation Pollution Food Cigarette Smoke Courtesy of Professor Bevin P.Engelward.Used with permission

Sunlight Pollution Oxidation Food Cigarette Smoke Courtesy of Professor Bevin P. Engelward. Used with permission

Images removed due to copyright reasons. Xeroderma Pigmentosum An Autosomal Recessive Disease 2000-fold increased risk of skin cancer

Xeroderma Pigmentosum An Autosomal Recessive Disease 2000-fold increased risk of skin cancer Images removed due to copyright reasons

Complementation in fused cells reveals 7 genes that cause Xeroderma Pigmentosum nucleus DNA Excision Repair after UV Irradiation No DNA Excision Repair after UV Irradiation cytoplasm ● ● ● WT XPA WT+XPA XPA XPA XPA+XPA ●● XPA XPB XPA+XPB

Complementation in fused cells reveals 7 genes that cause Xeroderma Pigmentosum nucleus = DNA Excision Repair after UV Irradiation cytoplasm = No DNA Excision Repair after UV Irradiation WT XPA WT + XPA XPA XPA XPA XPB XPA + XPB XPA + XPA WT XPA WT + XPA XPA XPA XPA XP XPA + XP XPA + XPA