DNA repair Flashcards
What happens if a DNA change is not caught before replication?
The mutation becomes permanent!
Cancer and many human diseases are the consequence of _________ and _________.
Mutation (due to DNA damage) and inadequate DNA repair.
What are 3 ways cancer can occur?
- Cascade effect: improper repair –> mutations. If this occurs in genes for repair or sensing/signaling damage you get genomic instability.
- If damage is in pathway for apoptosis or replication halting –> increased cancer risk.
If mutations occur in the ________, they can be inherited by the germline.
germline.
What happens when Cytosine is deaminated?
It becomes uracil. If it’s not repaired before replication, the opposing strand will receive an Adenine and the U will be replaced by T. Thus, GC –> AT
What are two examples of Direct Reversal?
- Ligation of a break in phosphodiester backbone
2. Repair of O6Methylguanosine by MGMT
Describe NER
Removes DNA lesions that distort structure (e.g. thymine dimers, bulky adducts). Endonuclease cuts the strand with the damage upstream & downstream of the site. Helicase (TFIIH) unzips DNA and bumps off single, bad segment which is then chewed up by exonucleases. Polymerase comes in and replaces nts using the other strand as a template, and ligase seals it.
What are the two types of NER, and what diseases result from deficiencies in these pathways?
Global Genome - fixes errors anywhere in genome. Disease: Xeroderma Pigmentosum
Transcription coupled - fixes errors only in regions that are actively transcribed. Disease: Cockayne Syndrome
Defects in NER contribute to what 3 diseases?
Cockayne Syndrome, Xeroderma Pigmentosum, and Trichothiodystrophy (TTD)
Describe BER
Specific glycolases recognize the mismatched base, flip it out, and cleave it off the sugar. The AP site is then removed by an endonuclease. A Polymerase fills the gap and a ligase seals it.
Describe MMR
Mismatched pair is recognized by MutS/MutL (MSH/MLH in eukaryotes). In bacteria, new strand isn’t methylated. In eukaryotes, new strand has nicks. Post-recognition, endonuclease cleaves the backbone, exonuclease chews away nts, and polymerase lays down new nts.
Defects in MMR machinery cause what disease?
Hereditary non-polyposis colorectal cancer
What is lesion bypass / when does it occur?
When cells continue replicating/dividing even in the face of immense DNA damage. Cells use crappy Pols that lack 3’–>5’ proofreading so it’s very error-prone
What are the two types of DSB repair?
Homologous Recombination (more accurate, requires homologous template) and Non-Homologous End Joining (less accurate, leads to deletions, insertions
What is the DNA damage checkpoint and who are the key players?
It halts cell cycle progression when damage is present to allow for time to repair. Key players are ATM & ATR, a pair of kinases that get recruited to sites of damage to then recruit and activate other downstream proteins. Disruption of this checkpoint leads to genomic instability and possible malignancy.
