4: genetics of cancer Flashcards
causes of damage to cell genomes?
-Errors during replication
- constant attack from endogenous biochemical processes
- Occasional attack from exogenons mutagens and their Metabolites
what kind of Errors during replication can happen?
- DNA pol has proofreading that digest faulty DNA → mutation in this domains can lead to earlier death
- mismatch repair (MMR)
what does the Mismatch repair?
copying repeated Sequences ?
- MMR enzymes monitor recently synthesized DNA to detect miscopied DNA Sequences
→ defects in MMR are responsible for accumulation of a variety of mutations
examples constant attack from endogenous biochemical processes?
- Depurination (most common)
- Base deamination
what happens with depurination?
the Beta-N- glycosidic bond between adenine or guanine and the deoxysibose is hydroyzed
when does Depurination occur?
when a purine base A or G is removed from the DNA deoxyribese backbone Via hydrolysis
what is Base deamination?
the removal of an amino group from a base.
Examp. → cytosine become s Uracil because of removal amino group
if uracil is not replaced it will become adenine in the new DNA strand during replication
examples of Exogenous mutagens?
- UV radiation → produces pyramidine dimers
- Reactive oxygen Species (ROS)
- chemical carcinogens
what causes the UV radiation?
pyramidine dimers → bond between adjecent pyrimidines in a strand / mostly thymine
-DisruptS normal pairing
- replication can not pas this lesion → cell will die When many are not repaired
What is Reactive oxygen species?
The striking of water by radiation causes it to lose an electron and become highly reactive
Result = Ros → reacts with DNA
What are chemical carcinogens?
-Base- modifying agents → alkylating agents
- DNA aducts
- Base an alogues → molecules that can substitute for normal bases in nucleic acids
what can Exogencus alkylating agents do?
covalently alter DNA bases by attaching alkyl groups → methyl groups
with what can DNA aducts interfere?
DNA transcription and replication and induce mutations
what can P53 do?
recieves info about genetic damage, May arrest the advance of the cell through its growth - and _ division cycle and orchestrate localiad responses in that cell to facilitate the repair of damage
damage to severe → may decide te signal apoptosis mechanism
What signals can induce P53 induction?
- U V radiation
- X-rays
- genotoxic agents
- inhibitors of DNA synthesis
- Agents that disrupt the microtubule of the ctoskelet
- hypoxia
how does p53 transcription factor work with MdM2?
key target of P53 is Mdm2 gene, When active as Tf it encourages the synthesis of Mdm2, the agent of it’s own destruction
- creates Negative feed back loop to ensure that P53 molecules are degraded → very low_steadu_state lends P53 proteins in normal, unperturbed cells
What happened with DNA damage → P53 accumulation to functional levels
- phosphorlation of amino acid in N-terminal domain
alters domain that is recognized and bound by Mdm2 → p53 protected from Mdm2 → no ubiquitlaten of P53 - DNA damage _activated ATM kinase phosphorylates Mdm2 that causes in acti vation and destabilization
Mobilization of repair Machinery (P53)
_ DNA damage in G1 leads to activation of P53
- P53 induces P21 cip 1
- p21 halts cell proliferation
- same time ‘ components of cellular DNA repair machinery are mobilized
- cells lacking functional P53 are unable to repair the DNA
function Base excisien repair (BER)?
- repair of lesions in DNA, derived from endogenous sources → Ros, depurination, deamination
- Repair enzymes DNA glycosylases
function Nucleotide EXcision repair (NER)?
- repair lesions creedted by Exogenous agents as photons and chemical carcinogens
- Repair enzymes that recognize bulky helix distorting lesions → PCNA and RPA
What is PCNA?
proliferating -cell nucleus antigen
What is RPA?
replication protein A, binds single-strand DNA
What are the 2 damage detection sub pathways?
- Global genomic NER → itmoves DNA damage anywheren in the genome
- Coupled NER (TC-NER) → specifically repairs transcription- blocking Lesions in actively transcribed DNA
features of homology directed repair (HR or HDR)?
- During late S phase and G2 phase of the cell cycle it uses sequences in the undamaged sister chromatic : homology
- RAD51,BRCA1 and BRCA2 are involved in these steps
