DNA Damage And Repair Flashcards
What are examples of exogenous causes of DNA damage?
-Thermal disruption
-UV light exposure
-Ionizing Radiation
-Exposure to mutagens, carcinogens, and viruses
What are examples of endogenous causes of DNA damage?
-Cellular metabolism
-Hydrolysis
-Nuclease digestion
What are outcomes of DNA damage?
-DNA repair, direct reversal
-DNA repair, excision. Repair
-Apoptosis (programmed. Cell death)
-Senescence (old cell)
- Cell with DNA. Damage retained. (Worse case)
What are the types of DNA damages?
-Single. Strand breaks
-Double strand breaks
-Pyrimidine. Dimer
-Nucleotide base oxidation
Examples of ionizing radiation are?
Gamma rays. And X-rays
What is the wavelength of UV-C rays?
~260 nm
What ultraviolet rays are absorbed by DNA?
UV-C, and UV-B
What are three chemical products in the environment that may cause DNA damage?
Hydrocarbons, aflatoxins, and chemotherapy
A source of hydrocarbon can come from…?
Cigarette smoke
Most error during DNA replication by error of?
Polymerase 3’ to 5’ exonuclease activity
MMR enzyme mutation. Caused ________
Mismatch repair failure
Highly - reactive oxygen radicals
A build up of reactive oxygen species in cells may cause damage to DNA, RNA, and proteins, and may cause cell death
The human genome project revealed ____ genes whose products participate in _____ _____.
130 genes, DNA repair
What is DNA photolyase?
Directly reverse cyclobutane pyrimidine dimer (CPD) via photochemical reactions. This is used in the natural repair system for pyrimidine dimers caused by UV damage.
What is excision repair?
Damaged base or bases removed and replaced with correct bases in a localized burst of DNA synthesis.
What is MGMT?
Stands for O^6-methylguanine-DNA methyltransferase. It prevents mismatch and errors during DNA replication and transcription.
What is the significance of the methylation state of MGMT gene promoter?
It determines whether tumor cells. Would response o temozolomide drug therapy.
In base excision repair, what enzyme removes incorrect nucleotides?
DNA glycosylase. There are at least 8 different genes encoding different DNA glycosylase.
In base excision repair (BER), what enzyme is responsible for replacing the missing nucleotide with the correct one?
DNA polymerase beta, one of at least 11 DNA polymerases encoded by genes.
What is required for the ligation of a break in the strand of DNA?
ATP is required.
Nucleotide. Excision repair repairs by…
Removing a large “patch” around the damage.
Example would be removing DNA damage induced by UV (thymine dimer)
In nucleotide excision repair what do Xp products do?
They repair DNA damage by cutting DNA both the 3’ side and 5’ side of the damaged area so tract containing damage can. Be removed.
In nucleotide excision repair, what enzymes are used to replace the wrong nucleotide with the correct one? This is after the wrong nucleotides have been removed.
Polymerase delta and polymerase epsilon
UV light may cause what in DNA?
Thymine dimer
What is xeroderma pigmentosum (XP)?
Rare inherited autosomal recessive disease of humans in which a deficiency of excinuclease occurs. It manifest as skin discoloration and multiple tumors on exposure to UV light.
What could cause xeroderma pigmentosum?
Mutations in several genes, XPA, XPB, XPF, and XPG which play a role in nucleotide excision repair (NER)
Unrepaired pyrimidine dimmers in humans may lead to…
Melanoma
What is mismatch repair (MMR)
A system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage. In other words deal with correcting mismatching nucleotides.
What are important steps in mismatch repair (MMR)?
Recognition of mismatch using several proteins.
Cutting the mismatch out
What gene encodes the caretaker gene important in mismatch repair (MMR)?
MSH2 also known s MutS protin homologous 2
What gene encodes for the protein that helps cut out mismatch nucleotides in mismatch repair (MMR)?
MutL homologous. It forms a complex with MutS and MutH
Mutations in MutS, MutH, or MutL will predispose a person to inherit what kind of cancer?
Colon cancer
MutL, MutS, and MutH can also be called…
Tumor suppressor genes
Single Strand breaks are repaired by?
BER, NER, and MMR. They are all strand specific SSB repairing system
Double strand breaks (DSBs) are repaid by
Double strand breaks described as complete break in DNA. They are repaired by rejoining the DNA (direct joining) or homologous recombination.
A double strand breaks and DNA strands are joined together with some complementary nucleotide is what kind of joining?
Nonhomologous End-Joining (NHEJ)
What is homologous recombination?
Also known as homologous directed repair (HDR). Recombining chromatids during G2 or homologous chromosome in G1.
What are the two genes responsible for coding the proteins used in homologous recombination?
BRCA1 and BRCA2
If there are mutations in BRCA1 and BRCA2 that render protein produced defected this will predispose patients for?
Predispose women to breast and ovarian cancer
List the cell cycle in order
G0, G1, S, G2, Mitosis (M)
What are the cycles within M (mitosis) phase of the cell cycle? Put in order
Prophase, metaphase (checkpoint), anaphase, telophase, and cytokinesis
What are the three check points in the cell cycle?
G1, G2, and Metaphase of the M phase.
Describe G0
Resting phase where cell has left cycle and has stopped dividing
Describe G1
Cells increase in size. The G1 checkpoint control mechanism happens to ensure everything is ready for DNA synthesis
Describe S phase of the cell cycle
DNA replication occurs during this phase
Describe G2 phase
Gap between DNA synthesis and mitosis continues. G2 check point happens to ensure everything is ready to enter the M (mitosis) phase and divide.
Describe M phase of the cell cycle
Cell growth stops and cellular energy s focused on the orderly division into two daught cells. Checkpoint in the middle of mitosis (metaphase) ensures cell is ready to complete cell division
What are the major proteins that control the cell cycle?
Cyclin-dependent protein kinases (Cdks) and cycling
Cdk-cyclin complex will do what?
Ability of Cdk to “P” target is dependent on the cyclin that it forms a complex with
In the cell cycle, P53-p21 activation will mean what?
Prevents cell from transitioning to the S phase (from G1).
Activation of cyclin D-cdk4 will do what?
Phosphorylation of retinoblastoma protein (pRb) in the nucleus.
If retinoblastoma protein (RB) remains unphosphorylated what will happen?
Unphosphorylated retinoblastoma will inhibit G1 by preventing E2F-mediated transcription
DNA damage during G2 phase will cause what to happen?
Initiates a signaling cascade that regulates wee1 and cdc25 activity, therefore controlling mitosis entry via cyclin B-cdk2 that can delay mitotic entry
What protein is responsible for ensuring chromosomes are properly attached to the spindle?
P53-cdk2-GADD45
If P53-cdk2-GADD45 is activate what will happen in the mitotic checkpoint of the cell cycle?
The cell will not go to the anaphase because the spindles are not properly connected to the chromosomes.
What s apoptosis?
Programmed cell death
What are some characteristics of a cell undergoing apoptosis?
Blabbing, cell shrinkage, nuclear fragmentation, chromatin condensation, chromosomal DNA fragmentation, and local mRNA decay
What are two significant apoptotic genes?
BCL2 and TP53
What is BCL-2 known for?
It’s role in inhibiting apoptosis (works with BAX and BAK) and promotes oncogenesis such as FL
What is follicular lymphoma (FL)?
Uncontrolled cell division of B-cells known as centrifuges and center oblasts. Cells normally occupy follicles in germinal centers of lymphoid tissues.
What are some evidence a cell is undergoing necrosis?
Increase cell volume
Loss of plasma membrane integrity
Leakage of cellular contents
What are clinical features of xeroderma pigmentosum?
Skin tumors, photosensitivity, cataracts, and neurological abnormalities
What are clinical features of cockayne syndrome?
Reduced stature, skeletal abnormalities, optic atrophy, deafness, photosensitivity, and mental retardation
What are clinical features of Fanconi anemia?
Anemia, leukemia susceptibility, limb, kidney, and heart malformations, chromosome instability
What are clinical features of bloom syndrome?
Growth deficiency, immunodeficiency, chromosome instability, increased cancer incidence
What are clinical features of Werner syndrome?
Cataracts, osteoporosis, atherosclerosis, loss of skin elasticity, short stature, diabetes, increase cancer incidence, sometimes described as premature aging
What are the clinical features of ataxia-telangiectasia?
Cerebella’s ataxia, telangiectases, immune deficiency, increased cancer incidence, and chromosome instability
Clinical features of hereditary nonpolyposis colorectal cancer?
Proximal bowel tumors, increased susceptibility to several other types of cancer.
