TY - JOUR

T1 - Loss of PICH Results in Chromosomal Instability, p53 Activation, and Embryonic Lethality

AU - Albers, Eliene

AU - Sbroggiò, Mauro

AU - Pladevall-Morera, David

AU - Bizard, Anna H.

AU - Avram, Alexandra

AU - Gonzalez, Patricia

AU - Martin-Gonzalez, Javier

AU - Hickson, Ian D.

AU - Lopez-Contreras, Andres J.

PY - 2018

Y1 - 2018

N2 - 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. 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.

AB - 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. 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.

KW - DNA damage

KW - Ercc6l

KW - genomic instability

KW - Pich

KW - UFBs

KW - ultrafine anaphase DNA bridges

KW - X chromosome inactivation

U2 - 10.1016/j.celrep.2018.08.071

DO - 10.1016/j.celrep.2018.08.071

M3 - Journal article

C2 - 30232008

AN - SCOPUS:85053129944

VL - 24

SP - 3274

EP - 3284

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 12

ER -