General CDK regulation: Cdc14 (humans TAZ) is a phosphatase that removes
Activating phosphorylation Inhibitory phosphorylation (these two necessary for M phase entrance in S. Pombe When no microtubuli attached to kinetocores: APC-Mad2 Cdh1 phosphate active Cdh1
securin-UB inhibition Cdh1-APC complex formation ubiquitylation of cyclin B (neccesity for M phase exit!)
CAK kinase stimulated by Wee1 reversed by Cdc25 (phosphatase) When microtubuli: APC free to bind Cdc20
Kleisin = Cohesin Cyclin B destruction surplus phosphatase (Cdc14 mainly) activity
Dephosphorylation of targets that caused mitotic preparation in prophase
Exit from of telophase: cytokinesis, retraction of microtubuli
Unlicensed ORIs Entrance of G1 phase
• G2/M phase (except telophase)
• Cdc6, Ctd1 phosphorylated by cyclin B-
CDK no MCM loading
Meta to anaphase transition
During prophase, Telophase to G1 transition
Cyclin B phosphorylates E3 Aka ‘mitotic exit network’
ubiquitine ligase
Ubiquitilation cyclin B itself: Spindle-assembly checkpoint
inactivation • Anaphase entry
Negative feedback loop Spindle-position checkpoint
• Telophase entry Exit of the G0 phase
• Addition of growth factors Via c-Jun, c-Myc, Fos signals gene transcription
G2 to M-phase transition CDK2 transcribed (activity controlled by p27 and p21) p21 under p53 stim
ORI licencing
• Leads to transcription of E2F and
DNA damage checkpoint 4 • Late telophase, early G1
During G0:
• M phase entry • Low cyclin B activity due to
• No CDKs or cyclins produced
ubiquitylation by formed
Mitotic cyclin-CDKs Cdh1-APC complex
Intra S-phase checkpoint • Cyclin A-CDK1 • Unphosphorylated Cdc6 and
• M phase entry • Cyclin B-CDK2 CD1 can be loaded
(major) • Loading MCM to ORC possible
= license
Mid-G1 to late-G1 to S transition
INK4 family: CKI specific for G1
Mid-G1 cyclin-CDKs Cyclin D inhibition by antigrowt
• Cyclin D-CDK4
CIP family of CKI’s active in S/G2/M • Cyclin D-CDK6
• P21: DNA damage response
• P27:
• p57
DNA damage checkpoint 1
• G1 phase
Late-G1 cyclin-CDKs
• Cyclin E-CDK2
S-phase cyclin-CDKs
• Cyclin A-CDK2
Cell signalling cascades
DNA damage checkpoint 3
• S phase G1 to S transition: passage through restriction
DNA damage checkpoint 2 point (yeast, similar to INK4s in mammals)
Unlicensed ORIs • S phase entry
• Fired ORI’s have no MCM complex and
cannot load these because assembly of G1 cyclin:
Cdc6 and Cdh1 that has to happen first is
not possible, as these are already
phosphorylated by the first firing.
• Free Cdc6 and Cdh1 is not a target of cyclin
A-CDK2
Activating phosphorylation Inhibitory phosphorylation (these two necessary for M phase entrance in S. Pombe When no microtubuli attached to kinetocores: APC-Mad2 Cdh1 phosphate active Cdh1
securin-UB inhibition Cdh1-APC complex formation ubiquitylation of cyclin B (neccesity for M phase exit!)
CAK kinase stimulated by Wee1 reversed by Cdc25 (phosphatase) When microtubuli: APC free to bind Cdc20
Kleisin = Cohesin Cyclin B destruction surplus phosphatase (Cdc14 mainly) activity
Dephosphorylation of targets that caused mitotic preparation in prophase
Exit from of telophase: cytokinesis, retraction of microtubuli
Unlicensed ORIs Entrance of G1 phase
• G2/M phase (except telophase)
• Cdc6, Ctd1 phosphorylated by cyclin B-
CDK no MCM loading
Meta to anaphase transition
During prophase, Telophase to G1 transition
Cyclin B phosphorylates E3 Aka ‘mitotic exit network’
ubiquitine ligase
Ubiquitilation cyclin B itself: Spindle-assembly checkpoint
inactivation • Anaphase entry
Negative feedback loop Spindle-position checkpoint
• Telophase entry Exit of the G0 phase
• Addition of growth factors Via c-Jun, c-Myc, Fos signals gene transcription
G2 to M-phase transition CDK2 transcribed (activity controlled by p27 and p21) p21 under p53 stim
ORI licencing
• Leads to transcription of E2F and
DNA damage checkpoint 4 • Late telophase, early G1
During G0:
• M phase entry • Low cyclin B activity due to
• No CDKs or cyclins produced
ubiquitylation by formed
Mitotic cyclin-CDKs Cdh1-APC complex
Intra S-phase checkpoint • Cyclin A-CDK1 • Unphosphorylated Cdc6 and
• M phase entry • Cyclin B-CDK2 CD1 can be loaded
(major) • Loading MCM to ORC possible
= license
Mid-G1 to late-G1 to S transition
INK4 family: CKI specific for G1
Mid-G1 cyclin-CDKs Cyclin D inhibition by antigrowt
• Cyclin D-CDK4
CIP family of CKI’s active in S/G2/M • Cyclin D-CDK6
• P21: DNA damage response
• P27:
• p57
DNA damage checkpoint 1
• G1 phase
Late-G1 cyclin-CDKs
• Cyclin E-CDK2
S-phase cyclin-CDKs
• Cyclin A-CDK2
Cell signalling cascades
DNA damage checkpoint 3
• S phase G1 to S transition: passage through restriction
DNA damage checkpoint 2 point (yeast, similar to INK4s in mammals)
Unlicensed ORIs • S phase entry
• Fired ORI’s have no MCM complex and
cannot load these because assembly of G1 cyclin:
Cdc6 and Cdh1 that has to happen first is
not possible, as these are already
phosphorylated by the first firing.
• Free Cdc6 and Cdh1 is not a target of cyclin
A-CDK2
