Mutation Repair + Epigenetics 1 Flashcards
What is base excision repair?
Base is removed and replaced with a DNA poilymerase and then a ligase sticks backbone together
What happens in nucleotide excision repair?
2 pathways:
Global Genomic Repair (GGR): Damaged strand recognized -> Damaged DNA sequence removed -> DNA polymerase repairs
Transcription-coupled (TC-NER): Damaged strand halts transcription at that point -> Proteins are recruited to form a stalled transcription complex -> Damaged strand removed -> damaged strand replaced
What kind of process is nucleotide excision repair?
Complex process requiring many proteins which cause disease if mutated (such as cockayne syndrome and xeroderma pigmentosum)
This process involves up to 30 nucleotides being removed from damaged strand
What kind of problems does nucleotide excision repair fix?
Removes bulky lesions such as pyrimidine dimers and other mutations causing distortions in DNA structure
How important is nucleotide excision repair?
It is a highly conserved pathway from bacteria to man which makes it very important for DNA fidelity
Which proteins are damaged in cockayne syndrome?
The proteins that form a complex with RNA polymerase during transcription
What proteins are damaged during xeroderma pigmentosum?
The helicase proteins that are part of the TFIIH complex which is important for DNA polymerase acitivty during nucleotide excision repair
What is TFIIH?
A large protein complex (10 subunits) which has DNA polymerase activity during nucleotide excision repair
What is RPA?
A single stranded DNA-binding protein that binds to template strand for nucleotide excision repair
Which DNA is most often repaired by nucleotide excision repair mechanisms?
Actively transcribed genes, this is because repair is coupled to transcription.
Why is nucleotide excision repair so necessary?
Lots of eukaryotic cells don’t divide and so DNA can’t be repaired in same way as bacteria.
Which strand is repaired more quickly?
The template strand. Lesions in other strand are not repaired as quickly because they will be repaired before DNA replication.
What happens if both DNA strands are damaged so that one cannot act as a template in repair?
Different repair mechanisms are used:
Either through non-homologous end joining
or Homologous directed repair
What kind of mutagens cause double stranded DNA damage?
Ionising radiation results in double strand breaks.
Interstrand crosslinks result when 2 DNA strands become covalently bonded which is highly toxic because it causes replication blocks.
What kind of medication cause crosslinks?
Chemotherapeutic drugs
What is homologous directed repair (aka strand dependent annealing)?
Homologous chromosome is used as a template for repair.
Error-free repair of double strand breaks
How does HDR occur?
End trimming by 5’ endonuclease exposes ssDNA overhangs coated by SSB forming nucleoprot filaments
Sister chromatid is disconnected and the damaged DNA uses that disconnected strand as a template strand for new DNA synthesis
DNA synthesis occurs on both strands to fill overhangs with the correct DNA in the 5’ - 3’ direction.
Ligation seals the gap
What is the consequence of defective DNA repair?
It is a cause for a few genetic diseases.
Affects a wide variety of body systems
Share constellation of common traits, notably a predisposition to cancer
What are the symptoms of xeroderma pigmentosum?
Freckle-like spots on skin, extreme sensitivity to UV light
Predisposition to skin cancer
Defect in nucleotide excision repair (proteins that bind to RNA polymerase when it is stopped)
What are the symptoms of cockayne syndrome?
Dwarfism
Sensitivity to light
Premature aging (fatal)
Deafness
Eye disorders
Mental retardation
Defect in nucleotide excision repair (TFIIH helicase proteins)
What does epigenetics mean?
The structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states
How does epigenetics get controlled?
Chemical tags are added or subtracted on DNA nucleotides/histones:
DNA methylation
Histone acetylation
Phosphorylation
Ubiquitination
How are epigenetics inherited?
Some genetic tags are passed down through generations. (Some tags are removed from chromsomes during zygote formation but some remain which make some traits heritable)
What are the implications for epigenetics in identical twins?
Epigenetic tags form on each twin resulting in different traits with age.
Epigenetic tags can have such a huge effect on twins that one can develop a disease while the other does not.
