@article{44394e36b2d94e87a0a6516a57f48084,
title = "Centrosome defects cause microcephaly by activating the 53BP1-USP28-TP53 mitotic surveillance pathway",
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.",
keywords = "DNA damage, TP53 activation, centrosome, microcephaly, mitotic surveillance pathway",
author = "Phan, {Thao P.} and Maryniak, {Aubrey L.} and Boatwright, {Christina A.} and Junsu Lee and Alisa Atkins and Andrea Tijhuis and Spierings, {Diana C.J.} and Hisham Bazzi and Floris Foijer and Jordan, {Philip W.} and Stracker, {Travis H.} and Holland, {Andrew J.}",
note = "Funding Information: The research grant supporting this project was terminated by March of Dimes one year after the project began (FY17-698, https://www.nature.com/articles/d41586-018-05875-7). We are grateful to Jeremy Nathans, Antony Rosen, and the Johns Hopkins Institute for Basic Biomedical Sciences for providing bridge support to allow the completion of this work. We also thank the members of the Nathans and Mueller laboratory for their valuable insights and technical support. This work also was supported by the National Institutes of Health grants R01GM114119 and R01GM133897, an American Cancer Society Scholar grant RSG-16-156-01-CCG, and an American Cancer Society Mission Boost Grant MBG-19-173-01-MBG (to A.J.H). T.P was funded by the National Institutes of Health training grant (T32GM007445). Funding Information: The research grant supporting this project was terminated by March of Dimes one year after the project began (FY17‐698, https://www.nature.com/articles/d41586‐018‐05875‐7 ). We are grateful to Jeremy Nathans, Antony Rosen, and the Johns Hopkins Institute for Basic Biomedical Sciences for providing bridge support to allow the completion of this work. We also thank the members of the Nathans and Mueller laboratory for their valuable insights and technical support. This work also was supported by the National Institutes of Health grants R01GM114119 and R01GM133897, an American Cancer Society Scholar grant RSG‐16‐156‐01‐CCG, and an American Cancer Society Mission Boost Grant MBG‐19‐173‐01‐MBG (to A.J.H). T.P was funded by the National Institutes of Health training grant (T32GM007445). Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2021",
month = jan,
day = "4",
doi = "10.15252/embj.2020106118",
language = "English (US)",
volume = "40",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Nature Publishing Group",
number = "1",
}