Genetics Lecture (9) PDF

Genetics DNA REPAIR LECTURE (9) DR. El-Sawy 0  Genetics DNA REPAIR Def  Permanent change of...

Genetics DNA REPAIR LECTURE (9) DR. El-Sawy 0  Genetics DNA REPAIR Def  Permanent change of base sequence of nucleotides.  Acc. to size: Types a. Gross at chromosome level. b. Small at DNA level. Spontaneous mutations Induced mutations Uncorrected replication Caused by external mutagens: Classes errors 1. Physical 2. Chemical 3. Biological Def : Physical, chemical or biological agent can cause mutation. Types : 1. Ionizing radiation: gamma & X-rays. 2. Non ionizing ration Physical a) UV radiation b) Electromagnetic radiation (Mobile phone, Satellite & computer). Chemical Cigarette smoke. (carcinogens) A. VIRUSES:  Hepatitis C Virus (HCV) → Heptocellular carcinoma (HCC) Biological  Human papiloma virus (HPV) → cancer cervix B. Bacteria: H. pylori → gastric cancer (Cancer Stomach) DR. El-Sawy 1  Genetics DNA REPAIR Types of DNA damage: Mutagens may lead to: 1. Break of phosphate diester bond in the DNA backbone. 2. Altered bases or deleted bases : Change of one codon to another for the same Silent amino acid. mutations So no effect on protein production. Point Mutations Change of one codon to another for a different Missense (base mutations amino acid. substitution) Nonsense Change a normal codon to termination codon mutations Change a termination codon to one that codes Sense mutations for amino acids. 3. UV → adjacent pyrimidines become joined covalently → Thymine dimers (which cause a kink or distorsion in DNA helix).  If the damage is not repaired: Permanent mutation occurs which may result in a hereditary disorder. DR. El-Sawy 2  Genetics DNA REPAIR Concept of DNA repair: 1. Enzymes scan their DNA for damage and initiate repair processes. 2. DNA repair process involves the recognition, removal and re-synthesis of DNA. 3. Endonucleases, Exonucleases, DNA polymerase and a ligase are required for repair. Steps : Recognition of  This is the function of an endonuclease. lesion :  Cleaves the damaged strand to form a cut (nick). ‫اتعرف‬ Excision of  Damaged part is removed by exonuclease. damaged DNA : ‫اشيل‬ Filling of gap with correct  By DNA polymerase beta. nucleotide : ‫املي‬ Ligation :  By DNA ligase. ‫اربط‬ DR. El-Sawy 3  Genetics DNA REPAIR Mechanisms of DNA Repair: 1. Mismatch repair (replicative errors). 2. Excision repair (correct the effect of exogenous agents). a. Base excision repair (BER). b. Nucleotide excision repair (NER). DR. El-Sawy 4  Genetics DNA REPAIR  Corrects errors occurring during DNA replication. Functions  By removing the mismatch nucleotide and resynthesize DNA strand with correct nucleotides. 1. DNA Mismatch Repair nuclease (endo then exo) complex: Recognizes, binds to, and excises damaged base or bases. 2. DNA polymerase: Enzymes Fills in the gap using the undamaged complementary strand of DNA as a template. 3. DNA ligase: Seals the break left by DNA polymerase  Hereditary Non-Polyposis Colon Cancer (HNPCC): Disease Results from defects in DNA mismatch repair. DR. El-Sawy 5  Genetics DNA REPAIR  It corrects DNA damage caused by exogenous agents either Functions chemical or physical.  The most common type of repair. Base excision repair Nucleotide excision repair (BER) (NER)  UV errors that induce thymine- For  X-ray errors (Base errors). thymine dimer.  Chemical mutagens  Recognize specific lesions in  Recognize and remove : DNA. a. Larger defects ,  Can correct only damaged Enzymes b. Thymine dimers bases that can be removed  By using UV-specific nicking by specific DNA endonulease enzyme glycosylase. Figure DR. El-Sawy 6  Genetics DNA REPAIR a. Cancers. b. Xeroderma Pigmentosum (XP): Def  It is a rare autosomal recessive disease (AR).  Absence of UV-specific endonuclease enzyme Cause  Defective correction of thymine dimmer (Nucleotide excision repair defect).  Marked sensitivity to sun light (ultraviolet) with subsequent Characterized by development of: 1. Skin damage. 2. Multiple skin cancers. 3. Premature death. DR. El-Sawy 7