Developmentally regulated elimination of damaged nuclei involves a Chk2-dependent mechanism of mRNA nuclear retention.
The faithful execution of embryogenesis relies on the ability of organisms to respond to genotoxic stress and to eliminate defective cells that could otherwise compromise viability. In syncytial-stage Drosophila embryos, nuclei with excessive DNA damage undergo programmed elimination through an as-yet poorly understood process of nuclear fallout at the midblastula transition. We show that this involves a Chk2-dependent mechanism of mRNA nuclear retention that is induced by DNA damage and prevents the translation of specific zygotic mRNAs encoding key mitotic, cytoskeletal, and nuclear proteins required to maintain nuclear viability. For histone messages, we show that nuclear retention involves Chk2-mediated inactivation of the Drosophila stem loop binding protein (SLBP), the levels of which are specifically depleted in damaged nuclei following Chk2 phosphorylation, an event that contributes to nuclear fallout. These results reveal a layer of regulation within the DNA damage surveillance systems that safeguard genome integrity in eukaryotes.
Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada.
Carole
C
Iampietro
Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada.
Julie
J
Bergalet
Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada.
Xiaofeng
X
Wang
Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada.
Neal A L
NA
Cody
Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada.
Ashley
A
Chin
Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Département de Biochimie, Université de Montréal, Montréal, QC H3T 1J4, Canada.
Fabio Alexis
FA
Lefebvre
Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada.
Mélanie
M
Douziech
Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada.
Henry M
HM
Krause
Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Département de Biochimie, Université de Montréal, Montréal, QC H3T 1J4, Canada; Division of Experimental Medicine, McGill University, Montréal, QC H3A 1A3, Canada. Electronic address: eric.lecuyer@ircm.qc.ca.
Eric
E
Lécuyer
D000818:Animals; D030801:Animals, Genetically Modified; D036703:Blastula / Q000166:cytology; D002467:Cell Nucleus / Q000235:genetics*; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000196:embryology* / Q000235:genetics; D004625:Embryo, Nonmammalian; D006657:Histones / Q000235:genetics; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D029721:Drosophila Proteins; D006657:Histones; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C490155:SLBP protein, Drosophila; D064447:Checkpoint Kinase 2; C112435:lok protein, Drosophila