Lecture 3 Flashcards
Ch.2 DNA repair mechanisms and therapeutic strategies
What are the steps of detecting and repairing mismatches in the DNA?
First detection id sone by MutSalpha or beta. Then a nick is formed, the nucleotide is removed and the gap is filled by polymerase, ligase puts everything together
What is the difference in MSH between MutS alpha or beta?
MutS alpha: MSH 2 and 6
MutS beta: MSH 2 and 3
What is the consequence of a mismatch mutation in MMR gene?
It causes Lynch syndrome, or hereditary non-polyposis colorectal cancer. MMR mutation is autosomal dominant
What is the process of nucleotide excision repair?
The helix-distorting DNA lesion is removed (eg adducts). Which is either done via global genome or transcription coupled NER. The DNA is opened by helicases and endonucleases remove the desired part
What does a mutation in the NER genes lead to?
It causes Xeroderma pigmentosum (XP)
What is Xeroderma pigmentosum?
You are hypersensitive to sunlight and have a high risk of skin cancer
When is base excision repair used?
When nucleotides are damaged due to intracellular processes eg 8-oxo-guanine. Or to repair ssDNA breaks
What is the process of base excision repair (BER)?
DNA glycosylase detects the site (get abasic site when only the base is removed), endonuclease then cleaves the backbone and flap endonuclease removes the flap
What is MUTYH?
It is a DNA glycosylase that repairs 8-oxo-guanine
What is the consequence of a mutation in MUTYH?
You get MUTYH associated polyps or familial adenomatous polyposis type 2. Thus a higher risk of colorectal cancer
Which 4 different ways are there to repair dsDNA breaks?
Non-homologous or alternative end-joining, also single-strand annealing and homologous recombination
What does the single-strand annealing rely on?
It relies on homologous repeat consequences, it leads to deletion
What is needed for homologous recombination?
Need a template from the sister chromatid
What is the process of homologous recombination?
ATM senses a break, exonuclease of the MRN complex digests the damaged strands to expose the ss regions. RAD51 then searches for homology. Resolvase is also involved in restoring
Which cancer predisposition syndromes are related to repairing dsDNA breaks?
Ataxia telangiectasia (leukemia and lymphoma), nijmegen breakage syndrome (lymphoma), bloom’s syndrome (all), BRCA1/2 (breast, ovary, pancreas)
Why are BRCA1 carriers promising for therapy?
There is a defect in homologous recombination in the tumor, but not in the normal cell
When is an intrastrand crosslink repair done?
Also called Fanconi Anemia , it’s a dsDNA break during cell division
How do repair an intrastrand crosslink and what are the consequences/risks?
Repair is done via homologous recombination. Is a consequence of chemo and have a higher risk of leukemia, head/neck cancer
How do you combat cancer?
By inducing DNA damage
How many cancer patients usually get radiotherapy?
About 50 percent
What are adverse events of radiotherapy?
Toxicity in normal cells, carcinogenic, therapy resistance
What is the benefit of ionizing radiation?
It can be a cure and give diagnostic information
What is the risk of ionizing radiation?
Tissue or organ injury, teratogenic, genetic and carcinogenic effects
What does the chemotherapy platinum-based drug do?
It induces crosslinks (eg cisplatin and carboplatin)
What does the chemotherapy alkylating agents do?
It adds DNA adducts via alkyl, requires metabolic activity (eg chlorambucil)
What does the chemotherapy antimetabolites do?
They mimic endogenous substances, inhibit nucleic acid synthesis (eg methotrexate and 5FU)
What does the chemotherapy topoisomere inhibitor do?
It increases the risk of DNA breaks (eg doxorubicin)
What does the chemotherapy mitotic spindle poison do?
It prevents mitotic activity (eg vincristine)
What is done with hormone therapy?
Cancers that need hormones for growth are targeted
Which drug can interfere with hormone synthesis?
Aromatose inhibitor, which prevents adrogen to estrogen conversion
Which drug can block the hormone receptor?
Tanoxifen to the ER to prevent estrogen binding
How can intrinsic drug resistance occur?
The tumor cell is heterogenous (different sensitivity due to a mutation in the cancer stem cell). Or due to the distance from the blood vessel and the vascular density. Also hypoxic cells are radio-resistant and debolished drug
How can acquired resistance occur?
Due to a higher drug efflux by the cancer cells or prevention of drug influx. Or amplifying of the target to outcompete the drug. Also modify the metabolism of the drug so it cannot become active. May enhance capacity to degrade the drug
What is synthetic letahlity?
A mutation of 2 genes combined is lethal eg BRCA1 and PARP inhibitor (use it to kill the cancer cells)
