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DNA repair. Lecture 13 Pp 209-215. DNA repair. Damaged DNA must be repaired If the damage is passed on to subsequent generations, then we use the evolutionary term - mutation . It must take place in the germ cells - the gametes - eggs and sperm
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DNA repair Lecture 13 Pp 209-215
DNA repair • Damaged DNA must be repaired • If the damage is passed on to subsequent generations, then we use the evolutionary term - mutation. It must take place in the germ cells - the gametes - eggs and sperm • If damage is to somatic cells (all other cells of the body bar germ cells) then just that one individual is affected.
Damage from where? • Consequences of DNA replication errors • Chemical agents acting on the DNA • UV light imparting energy into DNA molecule • Spontaneous changes to the DNA
Why repair DNA? • DNA pol does a great job, but not good enough • Introduces errors in about 1 in 10E7 nucleotides added, which it does not correct • Other mechanisms exist (as we will see) to correct many of the errors left by the replication system • Most mistakes and damage corrected (99% -leaving just a few - only 1 in 10E9 errors are left) • Mutations are permanent changes left in the DNA
Why repair DNA? • Repair of non-replication related damage to the DNA must also be a priority for the cell. • These defects also will prevent translation and duplication of the DNA • Cell will die. • Again, any errors or changes to the DNA become Mutations - which are permanent changes left in the DNA
Sickle Cell Disease • This is a very good illustration of the devastating effects of even tiny changes to the DNA • Red Blood Cells • Hemoglobin - • Has a large protein component • 2 beta globin chains • A single base change -substitution causes the disease
Spontaneous Mutations • Involves thermal energy • Due to random molecular collisions between molecules and DNA in the cell • Cannot be prevented • Parts of the DNA molecule are stripped off and alterations introduced • Many outcomes…
Direct DNA Damage • Some agents damage DNA directly • Chemicals and light • Chemicals - alkylating agents • Methy and ethyl groups added to DNA bases • This type of damage can be repaired by direct reversal involving special enzymes • They remove the offending atoms and restore the base
DNA Damage • Just a few types of damage is repaired via simple reversal of the chemical change - • UV light induced dimers • Methylation of bases • Ethylation of bases • Large chemical groups added to the DNA • Most other damage require other systems…
06_24_radiation.jpg Random photons of ultraviolet (UV) light induce aberrant bonding between neighbouring pyrimidines (thymine & cytosine) bases on the same strand of DNA. The will prevent the replication machine from duplicating the DNA. The cell will die! This type of defect can be readily reversed by a process called photoreactivation. Visible light energy is used to reverse the defect (in bacteria, yeasts, protists, some plants, and some animals but NOT in humans)
Other forms of DNA damage • Deamination - An amino group of Cytosine is removed and the base becomes Uracil • Deamination - An amino group of Adenine is removed and the base becomes Hypoxanthine • Deamination - An amino group of Guanine is removed and the base becomes Hypoxanthine
And… • Depurination - the base is simply ripped out of the DNA molecule leaving a gap (like a missing tooth)…
Molecular level view- Remember these are random events 06_23_Depurination.jpg
DNA level view of the same two events as last slide 06_25_mutations.jpg
Which is which? • The cell has a big problem to overcome… • How does it tell which strand carried the correct information? • We think we know…
The cell has to pick the right strand to fix or else… 06_21_Errors corrected.jpg
The cell has a mechanism of identifying new strand synthesis by leaving nicks that DNA. There are enzymes which scan these new regions looking for errors 06_22_DNA mismatch.jpg
Correction mechanisms • Direct reversal of damage - Photoreactivation (bacteria, yeast, some vertebrates - not humans) Two thymines connected together by UV light. • Excision Repair - removal of defective DNA. There are three distinct types • 1) base-excision • 2) nucleotide-excision • 3) mismatch repair
base-excision • Presence of the Uracil in DNA is a great example of this type • Special enzymes replace just the defective base • 1 snip out the defective base • 2 cut the DNA strand • 3 Add fresh nucleotide • 4 Ligate gap
nucleotide-excision • Same as previous except that • It recognizes more varieties of damage • Remove larger segments of DNA (10 -100s of bases)
mismatch repair • Special enzymes scan the DNA for bulky alterations in the DNA double helix • These are normally caused by mismatched bases • AG • AC • CT • These are excised and the DNA repaired
06_26_three steps.jpg Basic mechanism is the same for all three types Remove damaged region Resynthesis DNA Ligate
Consider… • Sunlight - sunbathing or daily exposure • Impact of ozone depletion • Impact on different skin tones • Environmental degradation
Evolution acts on mutations • If we did not have mutation then we would all be the same! • Any changes in the environment would be deleterious to all members of the population equally • = There would be no evolution!!!! • But mutation does exist and it is supported by comparison of related organisms…