In this lecture we will discuss about DNA damage and repair.
Single strand DNA damage and repair includes
1) Thymine dimers or nucleotide excision repair
2) Base excision repair
3)Mismatched repair
Double strand DNA damage and repair includes
1)Homologous recombination repair
2) non- homologous end joining repair
Tumor suppressor genes
1)P53 gene
2) Rb gene
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DNA has two types of repair system
I. Single strand repair
II. Double strand repair
❖ Single Strand Repair
Single strand repair includes followings
★ Thymine Dimers Repair / Nucleotide Excision Repair
● Occurs in G1 phase
● Ultraviolet radiation causes formation of thymine dimers .
● Thymine Dimers = Adjacent thymines forms double covalent bond with each other
instead of H-bond with its complementary bases
● Thymine Dimers are eliminated from DNA by a nucleotide excision repair
mechanism.
● Steps involved in Nucleotide excision repair
➢ An excision endonuclease enzyme recognizes the thymine dimer and makes a nick
or cut in the phosphodiester bonds on both sides thymine dimer and removes
it.Because this enzyme nicks nucleotide so called nucleotide excision repair.
➢ DNA polymerase fills the gaps by synthesizing DNA in 5→3 direction using the
undamaged strand as a template
➢ DNA ligase seals the nicks by making phosphodiester bonds
Bridge to Pathology
● If thymine dimers are not removed due to defective excision endonuclease enzyme, it
causes autosomal recessive disorder known as xeroderma pigmentosum with
following clinical features
➢ Extreme UV sensitivity
➢ Excessive freckling
➢ Multiple skin cancers
➢ Corneal ulcerations
● xeroderma pigmentosum is diagnosed by measuring the enzyme excision
endonuclease in white cells of blood.
★ Base Excision Repair
● Occurs throughout the cell cycle
● Cytosine deamination converts cytosine into uracil in DNA molecule
● This uracil is recognized and removed from DNA by base excision repair i.e Uracil
must be absent in DNA
● Steps involved in Base Excision Repair
➢ Base specific uracil glycosylase removes the uracil and creates AP site i.e
Apyrimidinic site (Pentose sugar without pyrimidine base).Because it cuts the
base so called base excision repair. RECALL= Apurinic site → pentose
without purine base
➢ AP-endonuclease cuts phosphodiester bond of nucleotide from 5’ end while
AP-lyase cuts phosphodiester bond of nucleotide from 3’ end → release of
DNA damaged nucleotide
➢ DNA polymerase β fills the gap by synthesizing new nucleotides and DNA
ligase seals it.
★ Mismatched Repair
● Occurs through S phase
● During DNA replication there may be mismatched base pair that are usually undergo
proofreading by DNA polymerase but if still there is some mistakes these are
repaired by hMSH2 and hMLH1 genes activity
● These mismatched pair are recognized and removed from DNA strand by enzymes
encoded by hMSH2 and hMLH1 genes
● DNA polymerase and DNA ligase fill the gap and seal it respectively
Bridge to Pathology
● Deficiency in hMSH2 and hMLH1 genes leads to lynch syndrome also known
as HNPCC ( hereditary nonpolyposis colorectal cancer) → cancers of large
intestine → colon and rectum cancers.
❖ Double Strand Repair
Double strand repair includes following
★ Homologous Recombination Repair
● This mechanism requires two homologous DNA duplexes
● A strand from damaged dsDNA is repaired by using a complementary strand
as template from 2nd homologous dsDNA without any loss of nucleotide.
● Defective Homologous Recombination Repair causes breast/ovarian cancers
with BRCA1 mutation (breast cancer gene1) and fanconi anemia ( decrease
production of all types of blood cells due to defect in bone marrow)
★ Non-Homologous End Joining
● 2 ends of DNA fragments bring together to repair the double stranded breaks
● Homology is not required and some DNA may be lost because the removed part of
DNA are not synthesized again
● Defective Non-Homologous End Joining causes Ataxia-telangiectasia
❖ Tumor Suppressor Gene
★ P53 Gene
● P53 gene is responsible for security and if G1 phase has mutations, P53 acts
as a barrier and does not allow the cell to enter the S phase until mutations
are repaired but if these mutations are not corrected ,P53 gene induces
apoptosis.
● Defect in P53 gene causes Ataxia-telangiectasia, BRCA1 ,LI fraumeni
syndrome (increased risk of certain types of cancer) and many solid tumors.
★ Rb gene
● Rb gene is responsible for negative regulation (suppression) of mutated cell cycle through its ability to suppress the growth factors required for entry of cells from G1 phase to S phase.
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