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Phosphorylation of MCPH1 isoforms during mitosis followed by isoform-specific degradation by APC/C-CDH1

Lookup NU author(s): Dr Stephanie Meyer, Dr Michael Dunn, Dr Daniel Vidler, Professor Peter Blain, Dr Paul Jowsey

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

MCPH1 exists as two isoforms that regulate CDK1 activation and chromosome condensation during mitosis, with MCPH1 mutations causing primary microcephaly. MCPH1 is also a tumour suppressor protein, with roles in DNA damage repair/checkpoints. Despite these important roles, there is little information on the cellular regulation of MCPH1. We demonstrate that both MCPH1 isoforms are phosphorylated in a CDK1-dependent manner in mitosis and identify several novel phosphorylation sites. Upon mitotic exit, MCPH1 isoforms were degraded by the APC/C-CDH1 E3 ligase complex. APC/C-CDH1 target proteins generally have D-Box or KEN-Box ‘degron’ sequences. We show that MCPH1 isoforms are degraded independently, with the long isoform degradation being D-Box-dependent, whilst the short isoform was KEN-Box-dependent. Our work identifies several novel mechanisms regulating MCPH1 and also highlights important issues with several commercial MCPH1 antibodies, with potential relevance to previously published data.

Publication metadata

Author(s): Meyer SK, Dunn M, Vidler DS, Porter A, Blain PG, Jowsey PA

Publication type: Article

Publication status: Published

Journal: The FASEB Journal

Year: 2019

Volume: 323

Issue: 2

Pages: ePub ahead of Print

Print publication date: 01/02/2019

Online publication date: 30/01/2019

Acceptance date: 17/09/2018

Date deposited: 21/11/2018

ISSN (print): 0892-6638

ISSN (electronic): 1530-6860

Publisher: Federation of American Societies for Experimental Biology

URL: https://doi.org/10.1096/fj.201801353R

DOI: 10.1096/fj.201801353R

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