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Mitosis: Vertebrate Checkpoints

By Levi Clancy for Student Reader on
updated

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CheckpointOverview
DNA Damage AMidway 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 BAt 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 CMidway 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-PhaseAt 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 DAt 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.
Spindle Assembly

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).

  1. Mad1 and Mad2C form a tetramer that binds unattached kinetochores via the Mad1 subunit.

  2. Mad2C of the kinetochore-bound tetramer can transiently bind Free Mad2O.

  3. This transient interaction causes Mad2O to bind and inactivate Cdc20, and to convert from Mad2O→Mad2C.

  4. Mad2C-Cdc20 transiently interacts with additional free Mad2O.

  5. This causes Mad2O to bind and inactivate additional Cdc20, forming a second Mad2C-Cdc20.

  6. The cycle repeats and free Mad2O is quickly converted to Mad2C-Cdc20.

  7. Binding of microtubules to the kinetochore displaces Mad1-Mad2C tetramers.

  8. Free tetrameric Mad2C cannot bind Mad2O. Instead, free tetrameric Mad2C binds p31comet.

  9. p31 then binds the Mad2C of the Mad2C-Cdc20 complexes, resulting in release of active Cdc20.

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.

Spindle Position

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.