Molecular Basis of Disease PDF

Molecular basis of Disease Health Index – state wise  Disease: is defined as a verifiable, self-conscious sensation of dysfunction and/or distress that is felt to be limitless, menacing and aid-requiring (clinical definition) As per WHO, health is “a state of complete physical, mental...

Molecular basis of Disease Health Index – state wise  Disease: is defined as a verifiable, self-conscious sensation of dysfunction and/or distress that is felt to be limitless, menacing and aid-requiring (clinical definition) As per WHO, health is “a state of complete physical, mental and social well-being, not merely the absence of disease or infirmity”  Genetic aberrations Derailed Enzyme signalling malfunction Molecular basis of Loss of disease Receptor homeostasis malfunction Transport irregularities  At molecular level: Diseases are manifestations of proteins or RNA or DNA quality and quantity disorders  Maintaining the genetic stability of an organism is essential for its survival and normal maintenance – Therefore requires extremely accurate mechanism for replicating DNA – Also mechanisms for repairing the accidental damages that DNA continually suffers. Damage to DNA is any change that introduces a deviation from the usual double-helical structure. B. Lewin (Text book definition)  Factors causing DNA damage Endogenous Exogenous (Internal) (External) Errors in proof reading activity of Radiation DNA polymerase UV, X-rays Rare chemical modifications of Mutagenic Chemicals bases Smoke Food additives Byproducts of cellular metabolism Pesticides Reactive oxygen species Anthropogenic, can be easily avoided  Endogenous: Chemical fluctuations cause rare forms of bases This spontaneous shift between keto and enol forms or between amino and imino forms in nitrogen bases is called tautomeric shift. Tautomeric Shifts Affect Base-Pairing Reactive Oxygen Species Superoxide (O2.−), hydrogen peroxide (H2O2) hydroxyl radical (OH.) ROS Metabolic Reactive Oxygen Species O2.− is generated in ETC Subsequently reduced to H2O2 by superoxide dismutase (SOD). H2O2 can be further reduced to H2O by catalase or can spontaneously oxidize iron (Fe2+) to form the highly reactive OH.. Normally ROS is removed from the cells ROS Affect of radiation Hydrolysis of cytosine to a hydrate cause mis-pairing during replication Cross-linking of adjacent thymine forms thymidine dimers blocks DNA replication  Mutagenic chemicals Original base mutagen modified base pairing base possible mutation  Why repair If errors in DNA are not repaired – causes alterations in the DNA sequence, called mutations Mutations are two types – Somatic mutations: occur in somatic cells, affects only the individuals. Cancer – Germ-line mutations: Happens in haploid cells, passed on to the next generation (Hereditary) Genetic disorders  A gene mutation can result in: Loss of function Disrupts protein structure therefore, function e.g., genes involved in DNA repair, cell cycle control Gain of function Increase in the normal function e.g., Growth factor receptors  Types of Gene Mutations Include: –Point Mutations –Insertions –Deletions –Frameshift  The DNA sequence that codes for a protein has a start codon and a stop codon, which is usually called as a reading frame.  Point mutations A change in a single base pair can be called as point mutation. two types – Transition mutation is the exchange of a purine-pyrimidine base pair for the other purine-pyrimidine base pair: C≡G becomes T=A, or T=A becomes C≡G. Transversion mutation is the replacement of a purine-pyrimidine base pair with a pyrimidine-purine base pair, or vice versa.  In Protein coding sequences… Silent mutation: Is a nucleotide change that produces a codon for the same amino acid. Missense mutation: Is a nucleotide change that results in a different amino acid.  In Protein coding sequences… Nonsense mutation: change in the nucleotide sequence such that the triplet functions as a stop codon, terminating the protein.  Insertions and deletions Insertions: One or more base pairs are added to the normal (wild type) sequence. Deletions: Loss of one or more base pairs.  Frame shift mutations Deletions or insertions can alter the protein length  Mutations can cause disease Haemoglobin: Globin protein 2 alpha and 2 beta chains Heme pigment bonded to each chain Iron atom in each Heme can carry one oxygen molecule  Sickle cell anaemia is caused by point mutations beta globin gene Color blindness is also caused by point mutations on X- chromosome Boon in disguise: Sickle cell patients are immune to malarial infections Chromosome structure and chromosomal disorders Every human cell contains a full diploid genome – 22 homologous autosomal pairs, and the sex chromosomes comprising two X chromosomes in females and an X and a Y in males. – Haploid germline cells contain 23 chromosomes. Errors during cell division can lead to cells with chromosomal abnormalities – which can be categorised as numerical abnormalities – Resulting daughter cell contains too many or too few chromosome – or structural abnormalities  numerical abnormalities Ploidy: the number of sets of chromosomes in a cell, or in the cells of an organism. – Triploidy (three haploid sets of chromosomes) – Tetraploidy (4 sets) – Polyploidy (multiple) – Aneuploidy (Having different number than normal) This results from a phenomenon called non- disjunction – replicated chromosomes do not separate properly at cell division non-disjunction Aneuploidy  Trisomy disorders Trisomy 21 Trisomy 18 Down syndrome Edwards syndrome Mild to moderate Intrauterine growth retardation, low intellectual disability, characteristic facial birth weight, appearance, heart defects abnormally shaped weak muscle tone, head, small jaw and mouth, heart defects, Severe intellectual disability leukaemia, Alzheimer’s disease  Structural abnormalities Chromosomal translocation Abnormal crossovers JIE ZHENG: ONCOLOGY REPORTS 30: 2011-2019, 2013  Fusion proteins Abl-BCR is a fusion protein – can cause cancer Inheritance  Repair mechanisms DNA damage is managed by multiple repair mechanisms. Four major DNA repair mechanisms: – base excision repair Single strand repair – nucleotide excision repair – homologous recombination Double strand repair – non-homologous end joining base excision repair The enzyme uracil DNA glycosylase removes an accidentally deaminated cytosine in DNA. After the action of this glycosylase the sugar phosphate with the missing base is cut out by the sequential action of AP endonuclease and a phosphodiesterase. The gap of a single nucleotide is then filled by DNA polymerase and DNA ligase. The net result is that the U that was created by accidental deamination is restored to a C. nucleotide excision repair Multiple proteins (uvra, uvrb) recognizes pyrimidine dimer one cut is made on each side of the lesion by nuclease DNA helicase then removes the entire portion of the damaged strand. The gap is filled by Polymerase and ligase For bulk repairs  Double strand breaks are more dangerous when both strands of the double helix are broken, leaving no intact template strand to enable accurate repair Two mechanisms – non-homologous end joining – homologous recombination non-homologous end joining Ku proteins play central role – grasps the broken chromosome ends. – Other proteins holds the broken ends together while they are processed and eventually joined. Error prone quick fix homologous recombination Homologous recombination is a much more accurate type of double-strand break repair Here, the DNA is repaired using the sister chromatid as a template.