MAD2L2 helps mitotic cells take it slow

Listovsky and Sale describe how a protein slows cells’ passage through mitosis by delaying activation of the anaphase-promoting complex/cyclosome (APC/C).

As a subunit of DNA polymerase ζ, MAD2L2 helps cells replicate damaged DNA and resolve chromosomes undergoing homologous recombination. The protein has also been shown to inhibit the cell cycle–regulated ubiquitin ligase APC/C in vitro, though how it does so and what effect this has in vivo is unknown.

Once chromosomes are properly attached to the mitotic spindle, the APC/C targets proteins for degradation so that cells can segregate their chromosomes and exit mitosis. Listovsky and Sale found that cells lacking MAD2L2 degraded APC/C substrates prematurely and passed through mitosis quicker than wild-type cells.

To ensure that its substrates are degraded in the correct order, the APC/C is sequentially activated by two different proteins. CDC20 stimulates the ubiquitin ligase initially, but CDH1 then takes over to broaden the range of targets. Listovsky and Sale found that MAD2L2 bound to CDH1 and prevented it from associating with the APC/C early in mitosis. MAD2L2 itself was targeted for destruction by the APC/C and CDC20 at anaphase onset, freeing CDH1 to take over as the APC/C’s activator. In cells lacking MAD2L2, CDH1 activated the APC/C prematurely, thereby accelerating mitotic exit.

MAD2L2-deficient cells often segregated their chromosomes incorrectly, perhaps because the loss of MAD2L2 is a double whammy that affects DNA polymerase ζ as well as mitotic progression. Defects in replication or recombination can result in problematic replication intermediates that lead to inaccurate chromosome segregation. Due to the premature activation of the APC/C, MAD2L2-deficient cells would also have less time to fix these errors before they divide.