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APC7 mediates ubiquitin signaling in constitutive heterochromatin in the developing mammalian brain.
- Source :
- Molecular cell; vol 82, iss 1, 90-105.e13; 1097-2765
- Publication Year :
- 2022
-
Abstract
- Neurodevelopmental cognitive disorders provide insights into mechanisms of human brain development. Here, we report an intellectual disability syndrome caused by the loss of APC7, a core component of the E3 ubiquitin ligase anaphase promoting complex (APC). In mechanistic studies, we uncover a critical role for APC7 during the recruitment and ubiquitination of APC substrates. In proteomics analyses of the brain from mice harboring the patient-specific APC7 mutation, we identify the chromatin-associated protein Ki-67 as an APC7-dependent substrate of the APC in neurons. Conditional knockout of the APC coactivator protein Cdh1, but not Cdc20, leads to the accumulation of Ki-67 protein in neurons in vivo, suggesting that APC7 is required for the function of Cdh1-APC in the brain. Deregulated neuronal Ki-67 upon APC7 loss localizes predominantly to constitutive heterochromatin. Our findings define an essential function for APC7 and Cdh1-APC in neuronal heterochromatin regulation, with implications for understanding human brain development and disease.
Details
- Database :
- OAIster
- Journal :
- Molecular cell; vol 82, iss 1, 90-105.e13; 1097-2765
- Notes :
- application/pdf, Molecular cell vol 82, iss 1, 90-105.e13 1097-2765
- Publication Type :
- Electronic Resource
- Accession number :
- edsoai.on1393990031
- Document Type :
- Electronic Resource