Universität zu Köln

Phan, Thao P., Maryniak, Aubrey L., Boatwright, Christina A., Lee, Junsu, Atkins, Alisa, Tijhuis, Andrea, Spierings, Diana C. J., Bazzi, Hisham ORCID: 0000-0001-8388-4005, Foijer, Floris ORCID: 0000-0003-0989-3127, Jordan, Philip W., Stracker, Travis H. and Holland, Andrew J. . Centrosome defects cause microcephaly by activating the 53BP1-USP28-TP53 mitotic surveillance pathway. Embo J.. HOBOKEN: WILEY. ISSN 1460-2075

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Abstract

Mutations in centrosome genes deplete neural progenitor cells (NPCs) during brain development, causing microcephaly. While NPC attrition is linked to TP53-mediated cell death in several microcephaly models, how TP53 is activated remains unclear. In cultured cells, mitotic delays resulting from centrosome loss prevent the growth of unfit daughter cells by activating a pathway involving 53BP1, USP28, and TP53, termed the mitotic surveillance pathway. Whether this pathway is active in the developing brain is unknown. Here, we show that the depletion of centrosome proteins in NPCs prolongs mitosis and increases TP53-mediated apoptosis. Cell death after a delayed mitosis was rescued by inactivation of the mitotic surveillance pathway. Moreover, 53BP1 or USP28 deletion restored NPC proliferation and brain size without correcting the upstream centrosome defects or extended mitosis. By contrast, microcephaly caused by the loss of the non-centrosomal protein SMC5 is also TP53-dependent but is not rescued by loss of 53BP1 or USP28. Thus, we propose that mutations in centrosome genes cause microcephaly by delaying mitosis and pathologically activating the mitotic surveillance pathway in the developing brain.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Phan, Thao P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Maryniak, Aubrey L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Boatwright, Christina A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lee, Junsu UNSPECIFIED UNSPECIFIED UNSPECIFIED Atkins, Alisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Tijhuis, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Spierings, Diana C. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bazzi, Hisham UNSPECIFIED orcid.org/0000-0001-8388-4005 UNSPECIFIED Foijer, Floris UNSPECIFIED orcid.org/0000-0003-0989-3127 UNSPECIFIED Jordan, Philip W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stracker, Travis H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Holland, Andrew J. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-310914
DOI:	10.15252/embj.2020106118
Journal or Publication Title:	Embo J.
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1460-2075
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language LIGASE IV DEFICIENCY; STRAND BREAK REPAIR; RADIAL GLIAL-CELLS; DNA-REPAIR; NEURAL PROGENITORS; PROTEIN COMPLEX; NEURONS ARISE; NEUROGENESIS; APOPTOSIS; 53BP1 Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/31091