part 4 Flashcards
(6 cards)
What are DNA damage checkpoints?
What are their functions during cell cycle progression?
DNA Damage: function to ensure that damaged DNA is not replicated and passed on daughter cells.
Checkpoint sense damaged or incompletely replicated DNA and coordinate further cell cycle progression
What are the events that lead to the activation of the maturation promoting factor (MPF)?
What are the events that lead to termination of MPF activity?
Activation
1) Wee 1 kinase phosphorylates Csk1 at 3 sites (THr161, Tyr15, and Thr14)
2) Cdc25 dephosphorylates Thr14 and Tyr15 leaving a phosphate only at Thr161
3) Creates an active Cdk1
4) This active MPF can then trigger entry to M phase
Termination
1) Terminate at the end of mitosis by proteasome degradation of cyclin B due to its ubiquitination by APC/C
2) Followed by dephosphorylation of CDK1
How does Cdk4,6/cyclin D activity drive G1 progression?
What are the main targets of Cdk4,6/cyclin D and what are their roles in the regulation of transcription?
1) underphosphorylated Rb binds to members of the E2F family and represses transcription of E2F-regulated genes
2) Phosphorylation of Rb by Cdk4, cyclin D means disassociation from E2F
3) This stimulates expression of target genes leads to cell progression
Main targets of Cdk4/cyclin D is Rb/E2F complex
Compare the two different responses to DNA damage.
What are the checkpoint kinases and what role do they play in cell cycle arrest in response to DNA damage
1) ATR protein kinase is activated by single-stranded or non-replicated DNA. ATM activated by double-stranded or unreplicated DNA
2) ATR & ATM then phosphorylate and activate checkpoint and 2 protein kinases
3) Chk 1 & 2 phosphorylate and inhibit Cdc25 protein phosphates. Cdc25 requires to activate Cdk1 and 2 so inhibition leads to arrest at the DNA damage checkpoints G1, S, and G2
What’s MDM2’s role in the regulation of p53, both in the absence of DNA damage and when there are high levels of DNA damage.
How is p53 modified by MDM2?
Absence of DNA damage
1) p35 is degraded by proteasome due to MDM2 mediated ubiquination
2) Keeps p35 levels low
Presence of DNA damage
1) ATM and Chk2 phosphorylate p35 blocks MDM2-medited ubiquintiation
2) P35 levels rapidly increase and p35 activates transcription of the gene encoding the cdk inhibitor p21
3) Leads to inhibition of Cdk2/cyclin B or cyclin A and cell cycle arrest
What role does the spindle assembly checkpoint have in the metaphase to anaphase transition?
What would you expect to see if cells had mis-aligned chromosomes?
Spindle assembly checkpoints monitor chromosome alignment on the metaphase plate. Prevents activation of Ap/C until all chromosomes aligned on mitotic spindle
All chromosomes must be aligned before cell transitions into anaphase
Misaligned chromosomes would not over onto anaphase. Chromosome abnormalities - cancer.
