Regulated interaction of ID2 with the anaphase-promoting complex links progression through mitosis with reactivation of cell-type-specific transcription

Tissue-specific transcriptional activity is silenced in mitotic cells. Here the authors reveal a general phosphorylation-dependent mechanism of recognition for the anaphase-promoting complex (APC) substrates, and show that the APC targets ID2 during the establishment of post-mitotic transcription. Tissue-specific transcriptional activity is silenced in mitotic cells but it remains unclear whether the mitotic regulatory machinery interacts with tissue-specific transcriptional programs. We show that such cross-talk involves the controlled interaction between core subunits of the anaphase-promoting complex (APC) and the ID2 substrate. The N-terminus of ID2 is independently and structurally compatible with a pocket composed of core APC/C subunits that may optimally orient ID2 onto the APC(CDH1) complex. Phosphorylation of serine-5 by CDK1 prevented the association of ID2 with core APC, impaired ubiquitylation and stabilized ID2 protein at the mitosis-G1 transition leading to inhibition of basic Helix-Loop-Helix (bHLH)-mediated transcription. The serine-5 phospho-mimetic mutant of ID2 that inefficiently bound core APC remained stable during mitosis, delayed exit from mitosis and reloading of bHLH transcription factors on chromatin. It also locked cells into a mitotic stem cell transcriptional state resembling the pluripotent program of embryonic stem cells. The substrates of APC(CDH1) SKP2 and Cyclin B1 share with ID2 the phosphorylation-dependent, D-box-independent interaction with core APC. These results reveal a new layer of control of the mechanism by which substrates are recognized by APC.

Automated summary

This study reveals the interaction mechanism between the anaphase-promoting complex (APC) and the tissue-specific transcription factor ID2 during mitosis. It shows that phosphorylation plays a crucial role in regulating the association between ID2 and the core APC, thus affecting post-mitotic transcription.