By Levi Clancy for Student Reader on
|DNA Damage A||Midway through G1, ATM/R activates p53, which activates p21CIP, which blocks Mid-G1-Cyclin+CDK (Cyclin-D+CDK4 & CDK6) if DNA damage is detected.|
|DNA Damage B||At the start of S-phase, ATM/R activates: p53, which activates p21CIP, which blocks the late G1 cyclin (Cyclin E) and the S-Phase cyclin (Cyclin A) if DNA damage is detected; and Chk1/2, which blocks Cdc25A if DNA damage is detected. Cdc25A would otherwise activate the CDK2, which binds the late G1 cyclin (Cyclin E) and the S-phase cyclin (Cyclin A). Cyclin-E+CDK2 and Cyclin-A+CDK2 are needed to initiate S-phase.|
|DNA Damage C||Midway through S-phase, ATM/R activates: p53, which activates p21CIP, which blocks Cyclin A (S-Phase cyclin) if DNA damage is detected; and Chk1/2, which blocks Cdc25A if DNA damage is detected. Cdc25A would otherwise activate the CDK2, which binds Cyclin A. Cyclin-A+CDK2 is needed during S-phase.|
|Intra-S-Phase||At the cusp of G2 and M phase, ATR activates Chk1, which inactivates Cdc25C. Cdc25C would otherwise activate mitotic cyclins (Cyclin A and Cyclin B).|
|DNA Damage D||At the cusp of G2 and M phase, ATM/R activates p53, which activates p21CIP, which inactivates mitotic cyclins (Cyclin A & Cyclin B) if DNA damage is detected. Arrest in G2 allows DNA double-stranded breaks to be repaired before mitosis.|
In the spindle assembly checkpoint (aka metaphase checkpoint), mitotic arrest deficient 2 (aka Mad2) blocks metaphase until every single kinetochore has properly attached to spindle microtubules. Mad2 exists in an open conformation (Mad2O) and a closed conformation (Mad2C).
Just a few Mad1-Mad2C tetramers bound to kinetochores can generate enough Mad2C-Cdc20 to overcome p31 activity. Once all kinetochores have attached to microtubules (thus releasing all Mad1-Mad2C tetramers), p31 activity predominates and active Cdc20 is released from Mad2C. The active Cdc20 binds APC/C, and the APC/C-Cdc20 degrades securin, the inhibitor of separase. Free separase digests the Kleisin subunit of cohesin, breaking open the Smc1-Smc3-Kleisin ring and allowing sister chromatids to separate. Cohesin is a Smc1/Smc3/Kleisin heterotrimer that holds together sister chromatids, with Kleisin acting like a clasp.
The spindle position checkpoint (aka the chromosome segregation checkpoint) blocks the onset of telophase by inactivation of Cdc14. Cdc14 would otherwise activate Sic1 and the degradation of Cyclin B's by APC/C-Cdh2.