DNA Repair PDF

DNA Repair Learning outcome Identify text concept of DNA repair. Explain different mechanisms of DNA repair t Correlate different DNA repair defects with related diseases Contents of lecture DNA text repair: definition, mechanisms Diseases due to defect in DNA repair ...

DNA Repair Learning outcome Identify text concept of DNA repair. Explain different mechanisms of DNA repair t Correlate different DNA repair defects with related diseases Contents of lecture DNA text repair: definition, mechanisms Diseases due to defect in DNA repair  Case Scenario An 8-year-old female, born out of the second- degree consanguineous marriage presented with complaints of pigmented skin spots allover the body since the age of 1 year which gradually increased in size and number. She had a history of acute sunburn all over the body after sun exposure. The patient was advised biopsy and photoprotection. Biopsy revealed multiple skin cancers. The patient was put on chemotherapy for squamous cell carcinoma https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5234176/  Outcome Learning 1 Identify concept of DNA repair.  DNA repair is a collection of processes by which a cell identifies and corrects damage to DNA that encodes its genome Causes of DNA damage: Exogenous Endogenous Spontaneous in Physical agents: metabolism X-ray, U.V.R.s (ROS) Chemical agents: as During replication Nitrous acid Types of DNA damage: - Single base alteration e.g. Deamination ,alkylation, oxidation, deletion) - Two base alteration e.g. UV light – induced thymine-thymine dimer (pyrimidine dimer) which cause a kink or distortion in DNA helix. - Chain breaks e.g by ionizing radiation - Cross linking ❑These damages may occur as many as 1 million molecular lesions per day. ❑As a consequence, DNA repair process is constantly active , as it responds to damage in DNA structure. ❑ If the damage is not repaired, irreparable DNA damage (Permanent mutation) occurs which may result in a hereditary disorder.  Steps of DNA REPAIR 4 main steps 1-Recognition of the lesion (incision step): The damaged DNA is recognizd by an endonuclease, which cleaves (cut) the DNA strand on both sides of the damage 2-Excision of damaged DNA: The damaged part is removed by exonuclease. 3-Filling of the gap with the correct nucleotide: This is catalyzed by a DNA polymerase beta. 4-Ligation:This is catalyzed by DNA ligase  Outcome Learning 2 Explain different mechanisms of DNA repair  Mechanisms of DNA Repair The most common mechanisms of DNA repair are: 1-Mismatch repair (replicative errors). 2-Excision repair (correct the effect of exogenous agents) this mechanism includes: A-Base excision repair (BER). B-Nucleotide excision repair (NER).  I-Mismatch repair Mismatch repair corrects errors occurring during DNA replication. 1- During replication, specific enzymes scan the newly synthesized strand. 2- If mismatch is detected, it is cut by 3- Gap is filled by  II-Excision Repair ❑ Excision repair corrects DNA damage caused by exogenous agents either chemical or physical. (the most frequent DNA lesions) ❑ It includes : 1. Base excision repair (BER) for base errors e.g. errors caused by chemical mutagens. 2. Nucleotide excision repair (NER) for Ultra-violet damage that induces thymine- thymine dimer chemical mutagens  II-Excision Repair 1- BASE Excision Repair: DNA glycosylase recognize and remove abnormal base in the DNA (cleave N-glycosidic bond of the damaged base leaving abasic (AP) site. Nuclease excise abasic sugar DNA polymerase replace the proper base Ligase returns DNA to its original state (seals the break)  2- Nucleotide Excision Repair -Repair larger damage up to 30 bases -Common causes of such DNA damage include UV light –induced thymine-thymine dimer (pyrimidine dimer)  2- Nucleotide Excision Repair Repair larger damage up to 30 bases 1- Repair enzymes recognize the defect. 2- Nucleases cut DNA upstream and downstream of the defect (UV-specific nicking endonuclease) 3- The gap is filled by DNA polymerase 4- Ligated by DNA ligase  Outcome Learning 3 Correlate different DNA repair defects with related diseases Disease related to defect in Mismatch Repair Hereditary Non-Polyposis Colon Cancer (HNPCC) -Genetic disease of autosomal dominant inheritance. -Caused by a mutation in one of genes of the DNA mismatch repair system and confers a markedly increased risk for various types of cancer, particularly of the colon and the endometrium.  Diseases Related to defect in Nucleotide Excision Repair Such as: ❑xeroderma pigmentosum (XP) ❑some cancers ❑ Neurodegenerative diseases  Xeroderma Pigmentosum (XP) It is a rare autosomal recessive disease. It is due to absence of UV-specific endonulease enzyme and defective correction of thymine dimmer (Nucleotide excision repair defect). It is characterized by marked sensitivity to sun light (ultraviolet) with subsequent development of: skin damage, multiple skin cancers premature death.  Questions The enzyme UV-specific nicking The type of DNA polymerase endonuclease is used in what 2 used in DNA repair is method of repair? a) Alpha a) Base excision 1 b) Beta b) Nucleotide excision c) Gamma c) Mismatch repair d) Delta d) Replication errors 4 e) Omega e) Translation errors  References Lippincott’s illustrated reviews, Biochemistry, 6th edition, 2014. BRS Genetics, 1st edition, 2010. BRS Biochemistry, Molecular Biology and Genetics, 5th edition, 2010. https://www.khanacademy.org/test- prep/mcat/biomolecules/dna/v/dna-repair-1 https://www.khanacademy.org/test- prep/mcat/biomolecules/dna/v/dna-repair-2