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

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.

Heat shock factor 5 establishes the male germ-line meiotic sex chromosome inactivation through regulation of Smarca4

“…Meiosis is a necessary process in germline development, when paternal and maternal chromosomes undergo synapsis and recombination of the genome prior to producing haploid gametes [ 1 ]. During this process, diploid cells enter to the prophase of meiosis I, including leptotene, zygotene, pachytene, diplotene and diakinesis, to reach the meiotic divisions [ 2 ]. At the early pachytene stage of the male mammals, homologous autosomes are fully synapsed [ 3 ].…”

From metabolism to malignancy: the multifaceted role of PGC1α in cancer

“…Knocking down PGC1α in these cells promotes a pro-metastatic gene program and enhances metastasis in mice models ( 131 ). PGC1α upregulates the expression of inhibitor of DNA binding protein (ID2), which binds and inhibits a diverse array of bHLH transcription factors ( 136 ). The binding of ID2 suppresses the transcription factor TCF4, resulting in the suppression of metastasis-related genes including integrins, which are known to affect metastasis ( 131 , 137 ).…”

Elevated Id2 expression causes defective meiosis and spermatogenesis in mice

“…22 Furthermore, a recent study indicated that ID2 interacts with the anaphase-promoting complex to activate cell-specific transcription. 23 Despite these important findings, the functional role of ID2 in meiosis has not been investigated.…”

“…Interestingly, it has been proposed that the pachytene arrest caused by Ovol1 deletion in mouse testes is due to the increased expression of Id2 22 . Furthermore, a recent study indicated that ID2 interacts with the anaphase‐promoting complex to activate cell‐specific transcription 23 . Despite these important findings, the functional role of ID2 in meiosis has not been investigated.…”