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

Sang Bae Lee (), Luciano Garofano, Aram Ko, Fulvio D’Angelo, Brulinda Frangaj, Danika Sommer, Qiwen Gan, KyeongJin Kim, Timothy Cardozo, Antonio Iavarone () and Anna Lasorella ()
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Sang Bae Lee: Columbia University Medical Center
Luciano Garofano: Columbia University Medical Center
Aram Ko: Columbia University Medical Center
Fulvio D’Angelo: Columbia University Medical Center
Brulinda Frangaj: Columbia University Medical Center
Danika Sommer: Columbia University Medical Center
Qiwen Gan: Columbia University Medical Center
KyeongJin Kim: Inha University
Timothy Cardozo: NYU Langone Health
Antonio Iavarone: Columbia University Medical Center
Anna Lasorella: Columbia University Medical Center

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract 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 APCCDH1 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 APCCDH1 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.

Date: 2022
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DOI: 10.1038/s41467-022-29502-2

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