Loss of PICH Results in Chromosomal Instability, p53 Activation, and Embryonic Lethality

PICH is a DNA translocase necessary for the resolution of ultrafine anaphase DNA bridges and to ensure the fidelity of chromosomal segregation. Here, we report the generation of an animal model deficient for PICH that allowed us to investigate its physiological relevance. Pich KO mice lose viability...

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Bibliographic Details
Published in:Cell reports (Cambridge) 2018-09, Vol.24 (12), p.3274-3284
Main Authors: Albers, Eliene, Sbroggiò, Mauro, Pladevall-Morera, David, Bizard, Anna H., Avram, Alexandra, Gonzalez, Patricia, Martin-Gonzalez, Javier, Hickson, Ian D., Lopez-Contreras, Andres J.
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Cells, Cultured
Chromosomal Instability
DNA Damage
DNA Helicases - metabolism
Embryonic Development - genetics
Ercc6l
genomic instability
Mice
Pich
Tumor Suppressor Protein p53 - metabolism
UFBs
ultrafine anaphase DNA bridges
X chromosome inactivation
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Summary:PICH is a DNA translocase necessary for the resolution of ultrafine anaphase DNA bridges and to ensure the fidelity of chromosomal segregation. Here, we report the generation of an animal model deficient for PICH that allowed us to investigate its physiological relevance. Pich KO mice lose viability during embryonic development due to a global accumulation of DNA damage. However, despite the presence of chromosomal instability, extensive p53 activation, and increased apoptosis throughout the embryo, Pich KO embryos survive until day 12.5 of embryonic development. The absence of p53 failed to improve the viability of the Pich KO embryos, suggesting that the observed developmental defects are not solely due to p53-induced apoptosis. Moreover, Pich-deficient mouse embryonic fibroblasts exhibit chromosomal instability and are resistant to RASV12/E1A-induced transformation. Overall, our data indicate that PICH is essential to preserve chromosomal integrity in rapidly proliferating cells and is therefore critical during embryonic development and tumorigenesis. [Display omitted] •Pich is essential for embryonic development•Pich KO embryos exhibit DNA damage, p53 activation, and apoptosis•Pich heterozygous mice are born at sub-Mendelian ratios•Pich-deficient MEF are resistant to RASV12/E1A-induced transformation Albers et al. show that PICH is essential for mouse embryonic development and that PICH deficiency limits oncogenic-induced cellular transformation. These findings suggest that PICH activity is critical during events requiring rapid cell proliferation such as embryonic development and tumorigenesis.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2018.08.071