Learning Outcomes - Week 7 - DNA repair Flashcards
Define DNA damage
DNA damage is defined as any modification of DNA that changes its coding properties or normal function in transcription or replication
Define genome stability
Genome stability is a feature of every organism to preserve and faithfully transmit the genetic material from generation to generation or from one somatic cell to another
Base excision repair: what can DNA bases be damaged by?
What is this caused by?
List the 4 steps of base excision repair
1 & 2 in image
- Specific DNA glycosylases excise the
damage leaving an AP site - An AP endonuclease then cleaves the
damage site near the phosphate
backbone and a few bases are
removed - A DNA polymerase then fills in the gaps
- A DNA ligase then ligates the DNA back
together
Define nucleotide excision repair
- The major cause of nucleotide
damage is UV light – direct
photolesions comprising of
cyclopyramidine dimers and 6-4
photoproducts. - DNA crosslinks may also be caused
by chemotherapeutic agents and
ionizing radiation – cross-linking
bases with the opposite strand of
DNA or with proteins. - These lesions lead to distortion of
the DNA helix – blocking the
replicative DNA polymerase.
Nucleotide Excision Repair
- May be global genome (GG) or transcription coupled (TC).
Define mismatch repair
See image for initial info
Mismatch Repair: Strand slippage during replication results in mismatches - Can lead to microsatellite instability
Mismatch Repair: Proof-reading by polymerases
- Following replication, polymerases
use proof-reading to identify
nucleotides that are mismatched.
- The polymerases can then directly
excise and replace the incorrect
nucleotides.
- However if these errors are not
detected straight away MMR is
required to correct them
Define single-strand break repair
Define homologous recombination
Homologous recombination is a type of genetic recombination in which nucleotide sequences are exchanged between two similar or identical molecules of DNA
Define non-homologous end-joining
What is it needed for?
NHEJ is needed for class switch recombination at the immunoglobulin heavy chain locus
Define chromatin remodelling
Chromatin remodeling is the rearrangement of chromatin from a condensed state to a transcriptionally accessible state, allowing transcription factors or other DNA binding proteins to access DNA and control gene expression
Understand importance of gene stability
The maintenance of genomic stability is essential for cellular integrity to prevent errors from DNA replication, endogenous genotoxic stress such as reactive oxygen species (ROS) from cellular metabolism, and exogenous carcinogen insults; for example, ultraviolet light, ionizing radiation or DNA damaging chemicals
Understand that different forms of DNA damage require different methods of repair
Damage to different genes results in varying diseases. Each type of damage requires it’s own form of repair.
Understand how DNA repair gene mutations cause human syndromes. Give two examples
DNA lesions can alter the primary structure of the double helix thereby affecting transcription and replication. Erroneous repair of lesions can lead to mutations in the genome that can be inherited to daughter cells with deleterious consequences for individual’s health.
These can result in human syndromes such as Hutchinson-Gilford Progeria syndrome, or the Banf1 A12T mutation that leads to Nestor-Guillermo progeria syndrome
Understand DNA damage and repair as targets for cancer therapy
(See image for initial info)
‘Classical’ Chemotherapy Targets
DNA Synthesis
– Hydroxyurea, methotrexate
* DNA Damage
– Alkylating agents, cis-platinum
* DNA Repair
– Topoisomerase inhibitors
* Mitosis
– Microtubule inhibitors
* Nuclear hormone receptors
– Anti-estrogens (breast/ovary), anti-androgens (prostate)
b, c
(Example of a question that is very detailed and will not be asked)
Which of the following gene(s) are frequently defective in cancers and are
‘targeted’ by PARP inhibitors? Select all that apply.
(a) TP53 gene, which encodes the p53 tumour suppressor.
(b) BRCA1 gene
(c) BRCA2 gene
(d) FBXO5 gene.
(e) INS gene, which encodes insulin.
b, c
