Damage to DNA caused by replication errors or mutations may have serious consequences. The cell possesses an inbuilt system to repair the damaged DNA. This may be achieved by four distinct mechanisms (Table 24.2).
Base excision-repair
Nucleotide excision-repair
Mismatch repair
Double-strand break repair
Base excision-repair
The bases cytosine, adenine and guanine can undergo spontaneous depurination to respectively form uracil, hypoxanthine and xanthine. These altered bases do not exist in the normal DNA, and therefore need to be removed. This is carried out by base excision repair (Fig. 1).
A defective DNA in which cytosine is deaminated to uracil is acted upon by the enzyme uracil DNA glycosylase. This results in the removal of the defective base uracil. An endonuclease cuts the backbone of DNA strand near the defect and removes a few bases. The gap so created is filled up by the action of repair DNA polymerase and DNA ligase.
Fig. 1 : A diagrammatic representation of base excision-repair of DNA
Nucleotide excision-repair
The DNA damage due to ultraviolet light, ionizing radiation and other environmental factors often results in the modification of certain bases, strand breaks, cross-linkages etc. Nucleotide excision-repair is ideally suited for such large-scale defects in DNA. After the identification of the defective piece of the DNA, the DNA double helix is unwound to expose the damaged part. An excision nuclease (exinuclease) cuts the DNA on either side (upstream and downstream) of the damaged DNA. This defective piece is degraded. The gap created by the nucleotide excision is filled up by DNA polymerase which gets ligated by DNA ligase (Fig. 2).
Fig. 2: A diagrammatic representation of nucleotide excision-repair of DNA
Mismatch repair
Despite high accuracy in replication, defects do occur when the DNA is copied. For instance, cytosine (instead of thymine) could be incorporated opposite to adenine. Mismatch repair corrects a single mismatch base pair e.g. C to A, instead of T to A. The template strand of the DNA exists in a methylated form, while the newly synthesized strand is not methylated. This difference allows the recognition of the new strands. The enzyme GATC endonuclease cuts the strand at an adjacent methylated GATC sequence (Fig.3). This is followed by an exonuclease digestion of the defective strand, and thus its removal. A new DNA strand is now synthesized to replace the damaged one.
Fig. 3: A diagrammatic representation of mismatch repair of DNA
Double-strand break repair
Double-strand breaks (DSBs) in DNA are dangerous. They result in genetic recombination which may lead to chromosomal translocation, broken chromosomes, and finally cell death. DSBs can be repaired by homologous recombination or non-homologous end joining. Homologous recombination occurs in yeasts while in mammals, non-homologous and joining dominates.
Photoactivation Repair in E. coli
Exposing UV treated cells to blue light results in a reversal of the thymine dimer formation
Enzyme, photoactivation repair enzyme (PRE) absorbs a photon of light (from blue light) and is able to cleave the bond forming the thymine dimer. • Once bond is cleaved, DNA is back to normal.
Fig. 4: A diagrammatic representation of photoactivation repair
Here are some common inheritant mutation diseases-
Cystic fibrosis is an inherited condition that causes sticky mucus to build up in the lungs and digestive system. This causes lung infections and problems with digesting food.
In the UK, most cases of cystic fibrosis are picked up at birth using the newborn screening heel prick test.
Symptoms of cystic fibrosis
Symptoms of cystic fibrosis include:
recurring chest infections
wheezing, coughing, shortness of breath and damage to the airways (bronchiectasis)
difficulty putting on weight and growing
yellowing of the skin and the whites of the eyes (jaundice)
diarrhoea, constipation, or large, smelly poo
a bowel obstruction in newborn babies (meconium ileus) – surgery may be needed
People with the condition can also develop a number of related conditions, including diabetes, thin, weakened bones (osteoporosis), infertility in males, and liver problems.
Treatments for cystic fibrosis
There's no cure for cystic fibrosis, but a range of treatments can help control the symptoms, prevent or reduce complications, and make the condition easier to live with.
Huntington's disease is a condition that stops parts of the brain working properly over time. It's passed on (inherited) from a person's parents.
Symptoms: Symptoms of Huntington's disease can include:
movements of the limbs and body
breathing
Treatment and support: There's currently no cure for Huntington's disease or any way to stop it getting worse.
Sickle cell disease is the name for a group of inherited health conditions that affect the red blood cells. The most serious type is called sickle cell anaemia.
Sickle cell disease is particularly common in people with an African or Caribbean family background.
Symptoms: The main symptoms of sickle cell disease are:
painful episodes called sickle cell crises, which can be very severe and last for days or weeks
an increased risk of serious infections
anaemia (where red blood cells cannot carry enough oxygen around the body), which can cause tiredness and shortness of breath
Some people also experience other problems, such as delayed growth, strokes and lung problems.
Treatments: People with sickle cell disease need treatment throughout their lives. This is usually delivered by different health professionals in a specialist sickle cell centre.
Tay-Sachs disease is a rare inherited condition that mainly affects babies and young children. It stops the nerves working properly and is usually fatal.
Symptoms: The main symptoms include:
learning to crawl, and losing skills they
have already learnt
worse until they're unable to move (paralysis)
Treatments: There's currently no cure for Tay-Sachs disease. The aim of treatment is to make living with it as comfortable as possible.
Down syndrome is a genetic condition where people are born with an extra chromosome. Most people have 23 pairs of chromosomes within each cell in their body, for a total of 46. A person diagnosed with Down syndrome has an extra copy of chromosome 21, which means their cells contain 47 total chromosomes instead of 46. This changes the way their brain and body develop.
Symptoms: Down syndrome causes physical, cognitive and behavioral symptoms. Not all people with Down syndrome have all of these symptoms.
Physical signs of Down syndrome: They can include:
A flat nose bridge.
Slanted eyes that point upward.
A short neck.
Small ears, hands and feet.
Weak muscle tone at birth.
Small pinky finger that points inward towards the thumb.
One crease in the palm of their hand (palmar crease).
Shorter-than-average height.
Ear infections, Vision problems, Dental problems.
Cognitive symptoms of Down syndrome:
Walk and move (gross and fine motor skills).
Speak (language development skills).
Learn (cognitive skills).
Play (social and emotional skills).
Behavioral symptoms of Down syndrome:
Stubbornness and tantrums.
Difficulty paying attention.
Obsessive or compulsive behaviors.
Treatment: There’s no cure for Down syndrome, but treatment is available to help your child reach their full potential. Treatment focuses on helping your child thrive physically and mentally.
Hemophilia is a rare, inherited blood disorder that causes your blood to clot less, which results in an increased risk of bleeding or bruising.
Symptoms:
bruises after minor injuries. This is a sign
of bleeding under their skin.
time, whether that’s bleeding after surgery,
bleeding after dental treatment or simply
bleeding from a cut finger.
They may start bleeding for no apparent reason, such as sudden bloody noses.
How much bruising or bleeding people have depends on whether they have severe, moderate or mild hemophilia:
People with severe hemophilia often have spontaneous bleeding or bleeding for no apparent reason.
References:
Biochemistry by U. Satynarayana, U Chakrapani.
https://www.nhs.uk/
https://my.clevelandclinic.org/
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