Chapter 2 Flashcards
Which (epi)genetic alterations can lead to cancer?
- Stability genes inactivation (used for DNA repair)
- Oncogenes activation ( example: Growth factors)
- Tumor suppressor genes inactivation
Give examples of small changes in DNA
- Base pair substitution
- Deletions or insertions
- Single and Double strand breaks
Give examples of large changes in DNA
- Change in DNA content per nucleus
- Chromosome rearrangements
- Gene amplification
Why are strand breaks extremely dangerous?
They increase the risk of large deletions and major chromosome rearrangements
What are some exogenous causes of DNA damage?
- Smoking
- Drinking
- UV light
- Other forms of radiation
What are some endogenous causes of DNA damage?
- Mistakes in replication
2. Reactive oxygen species
Give some examples of DNA damage that could happen and their possible cause
- Pyrimidine dimer (UV light)
- Strand breaks (X-rays)
- Bulky adducts (PAH)
- Base loss (Spontaneous hydrolysis)
- Nitrogen crosslinks (cisplatin, MMC, nitrogen mustard)
- Intrastrand adducts (cisplatin)
- Modified bases (Alkylating agents, ROS)
How is 8-oxoguanine formed?
Through ionizing radiation or cellular aging
Why is 8-oxoguanine mutageninc?
DNA polymerase reads it as a thymine, and it will transcribe a thymine instead of guanine on the next strand
Give some examples of DNA repair mechanisms and when they are applied
- Base excision repair - When one base is damaged
- Nucleotide excision repair - When there are bulky adducts
- Mismatch repair - for replicaion errors
- Recombination repair - strand breaks
- complex repair - Cross-links
What are some recessive cancer-predisposition syndromes?
- Ataxia telangiectasia (defect in the ATM kinase)
- Fanconi anemia
- Xeroderma pigmentosum
- Nijmegen breakage syndrome
- Bloom’s syndrome
What are some dominant cancer predisposition syndromes?
- HNPCC (colon cancer)
2. BRCA1/BRCA2 (breast cancer, ovary cancer and pancreas)
What protein is important for the repair of double strand breaks?
Ataxia enzyme (ATM)
What are the steps in repairing a strand break?
The strand breaks. ATM gets activated. Exonuclease complex (RAD50/MRE11/NBS1) digest damaged strands. Digested strand binds to a homologous combination on an intact strand, then it’s being restored.
What are ATM, FA and BRCA proteins important for?
DNA repair and sensing of DNA damage.
Why are people with dysfunctional ATM, FA and BRCA at higher risk of developing cancer if they smoke and drink?
Because their body is less effective at repairing DNA damage
What is base excision repair and what is it used for?
BER is used to correct a base (pyrimidine/purine) that has been damaged. Only the base is removed
What is the role of DNA glycosylase?
It senses a damaged DNA base and removes it, leaving an abasic site
Which enzyme replaces the missing base in BER?
DNA polymerase beta
What is the role of MUTYH?
It is a DNA glycosylase that is involved in the repair od 8-oxoguanine
What is Nucleotide excision repair?
A stretch of nucleotides is removed and replaced. Usually the stretch is 25 ~ 30 base pairs long
What kind of damage induce NER?
UV-induced pyrimidine dimers and large chemical adducts
what disease is related to mistakes during NER?
Xeroderma Pigmentosum
What disease is related to mistakes in BER?
Familial adenomatous polyposis
Which proteins are involved in mismatch DNA repair?
MSH2 and MLH1
What cancer is related to dysfunctional MSH2 and MLH1?
HNPCC
Hereditary Non-Polyposis Colorectal Cancer
what is ionization radiation?
Radiation that can cause an atom to lose an electron
How can free electrons damage the DNA?
Through binding to other atoms in the DNA or by creating ROS
What is the most dangerous ROS?
Hydroxyl radical OH
what is the unit “Gray” ?
Gray is the absorbed dose in tissues
1 Gy = deposit of 1 joule/ kg tissue
What is the unit “Sievert”?
Sievert is used as an unit for biological damage
Sv = (dose in Gy) x radiation quality factor
Give some examples of Particle Radiation
- alpha (2p + 2n)
- deuteron (p + n)
- beta (electron)
- neutron
- proton
- heavy particles (carbon ions)
Give some examples of EM radiation
- Photons
- X-rays
- Gamma rays
What is Linear Energy Transfer?
The average energy per distance that a charged particle deposits in a tissue (keV/um)
The higher the LET…
… the more cells are getting killed per Gy
What is the latent period of cancer?
The mean time between exposure to radiation and the manifestation of a tumors
what is the Latency for leukemia after being exposed to radiation?
Around 10 ~ 15 years
what is the most frequent cancer induced by radiation?
Leukemia
Which age group is the most sensitive to radiation?
Children
What is an example of non-ionizing radiation?
UV radiation. It does not cause ionization, but it causes pyrimidine dimers and point-mutations
What is a genotoxic compound?
A compound that can induce DNA damage
How can non-genotoxic compounds promote cancer?
By stimulating cell proliferation
what are the most important DNA-damage inducing carcinogens?
- PAH
- Aromatic amines
- Nitrosamines
- Alkylating drugs
Where can you find nitrosamines?
In Tabacco smoke
Give some examples of anti-oxidants
Gluthatione
Vit A, C and E
What are some examples of alkylating agents?
- Chlorambucil
- Temozolomide
- Cyclophosphamide (has to be metabolized)
What are some platinum-based drugs?
Cisplatin and carboplatin
What are some antimetabolites?
Methotrexate
5-FU
what are some organic drugs?
Doxorubicin (topoisomerase II inhib)
Vincristine (microtubuli inactivator)
What are some examples of intrinsic drug resistance by cancer cells?
- Location in the body (distance from blood vessels) - Hypoxic cells are more resistant to radiation
- Heterogeneity - cells have different resistances to radiation and drugs
- Drug resistance can be acquired
