Autoren:	Matos-Rodrigues, Gabriel E. Grigaravicius, Paulius Lopez, Bernard S. Hofmann, Thomas G. Frappart, Pierre-Olivier Martins, Rodrigo A. P.
Titel:	ATRIP protects progenitor cells against DNA damage in vivo
Online-Publikationsdatum:	27-Apr-2021
Erscheinungsdatum:	2020
Sprache des Dokuments:	Englisch
Zusammenfassung/Abstract:	The maintenance of genomic stability during the cell cycle of progenitor cells is essential for the faithful transmission of genetic information. Mutations in genes that ensure genome stability lead to human developmental syndromes. Mutations in Ataxia Telangiectasia and Rad3-related (ATR) or in ATR-interacting protein (ATRIP) lead to Seckel syndrome, which is characterized by developmental malformations and short life expectancy. While the roles of ATR in replicative stress response and chromosomal segregation are well established, it is unknown how ATRIP contributes to maintaining genomic stability in progenitor cells in vivo. Here, we generated the first mouse model to investigate ATRIP function. Conditional inactivation of Atrip in progenitor cells of the CNS and eye led to microcephaly, microphthalmia and postnatal lethality. To understand the mechanisms underlying these malformations, we used lens progenitor cells as a model and found that ATRIP loss promotes replicative stress and TP53-dependent cell death. Trp53 inactivation in Atrip-deficient progenitor cells rescued apoptosis, but increased mitotic DNA damage and mitotic defects. Our findings demonstrate an essential role of ATRIP in preventing DNA damage accumulation during unchallenged replication.
DDC-Sachgruppe:	610 Medizin 610 Medical sciences
Veröffentlichende Institution:	Johannes Gutenberg-Universität Mainz
Organisationseinheit:	FB 04 Medizin
Veröffentlichungsort:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-5843
Version:	Published version
Publikationstyp:	Zeitschriftenaufsatz
Nutzungsrechte:	CC BY
Informationen zu den Nutzungsrechten:	https://creativecommons.org/licenses/by/4.0/
Zeitschrift:	Cell death & disease 11
Seitenzahl oder Artikelnummer:	923
Verlag:	Nature Publishing Group
Verlagsort:	London
Erscheinungsdatum:	2020
ISSN:	2041-4889
URL der Originalveröffentlichung:	https://doi.org/10.1038/s41419-020-03090-9
DOI der Originalveröffentlichung:	10.1038/s41419-020-03090-9
Enthalten in den Sammlungen:	JGU-Publikationen