@article{e6614eff7b954e509eb77e9b09d32b6f,
title = "APC7 mediates ubiquitin signaling in constitutive heterochromatin in the developing mammalian brain",
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.",
keywords = "APC7, Cdh1, Ki-67, anaphase-promoting complex, brain, chromatin, heterochromatin, neurodevelopment, ubiquitin, ubiquitin ligase",
author = "Ferguson, {Cole J.} and Olivia Urso and Tatyana Bodrug and Gassaway, {Brandon M.} and Watson, {Edmond R.} and Prabu, {Jesuraj R.} and Pablo Lara-Gonzalez and Martinez-Chacin, {Raquel C.} and Wu, {Dennis Y.} and Brigatti, {Karlla W.} and Puffenberger, {Erik G.} and Taylor, {Cora M.} and Barbara Haas-Givler and Jinks, {Robert N.} and Strauss, {Kevin A.} and Arshad Desai and Gabel, {Harrison W.} and Gygi, {Steven P.} and Schulman, {Brenda A.} and Brown, {Nicholas G.} and Azad Bonni",
note = "Funding Information: We thank the Bonni laboratory for critical feedback. We also thank C. Yuede, D. Wozniak, S. Conyers, J. Gunn, S. Joh, R. Lewis, M. Wallace, H. Stark, D. Haselbach, D. Pizzo, L. Kaube, D. Bolhuis, F. Meitinger, K. Williams, L. Poskitt, M. Young, and T. Morlet. This work was supported by the NIH grant NS051255 (to A.B.); NIH K08HD099314 (to C.J.F.); NIH R35GM128855 and UCRF (to N.G.B.); NIH R37GM065930 , NIH P30CA021765 and the Max Planck Society (to B.A.S.); NIH GM67945 (to S.P.G.); NIH T32GM008570 and NSF DGE-1650116 (to T.B.); NIH R01GM074215 (to A.D.); and NIH OD021629 (WUCCI). Funding Information: We thank the Bonni laboratory for critical feedback. We also thank C. Yuede, D. Wozniak, S. Conyers, J. Gunn, S. Joh, R. Lewis, M. Wallace, H. Stark, D. Haselbach, D. Pizzo, L. Kaube, D. Bolhuis, F. Meitinger, K. Williams, L. Poskitt, M. Young, and T. Morlet. This work was supported by the NIH grant NS051255 (to A.B.); NIH K08HD099314 (to C.J.F.); NIH R35GM128855 and UCRF (to N.G.B.); NIH R37GM065930, NIH P30CA021765 and the Max Planck Society (to B.A.S.); NIH GM67945 (to S.P.G.); NIH T32GM008570 and NSF DGE-1650116 (to T.B.); NIH R01GM074215 (to A.D.); and NIH OD021629 (WUCCI). C.J.F. and A.B. conceived the project. C.J.F. A.B. and H.W.G. wrote the manuscript. C.J.F. performed the imaging, biochemistry, and behavior experiments. O.U. conducted the experiments in mice and cell culture, under the supervision of C.J.F. T.B. R.C.M.-C. and N.G.B. conducted the in vitro assays with recombinant proteins. B.M.G. and S.P.G. performed TMT proteomics. E.R.W. J.R.P. and B.A.S. acquired and analyzed the cryo-EM data. P.L.-G. and A.D. performed the experiments in RPE-1 cells. D.Y.W. performed the informatics analysis. E.G.P. analyzed the clinical genetic data. K.W.B. and K.A.S. cared for the patients and analyzed the clinical data. C.M.T. and B.H.-G. performed the intelligence testing. The authors declare no competing interests. A.B. is an employee of Roche. B.S. is on the scientific advisory board of BioTheryX and Interline Therapeutics, a shareholder of Interline Therapeutics, and a co-inventor of intellectual property licensed to Cinsano. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2022",
month = jan,
day = "6",
doi = "10.1016/j.molcel.2021.11.031",
language = "English",
volume = "82",
pages = "90--105.e13",
journal = "Molecular Cell",
issn = "1097-2765",
number = "1",
}