New mouse model uncovers the relevance of Ultra-Fine DNA Bridge (UFB) resolution during embryonic development and tumorigenesis – University of Copenhagen

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26 September 2018

New mouse model uncovers the relevance of Ultra-Fine DNA Bridge (UFB) resolution during embryonic development and tumorigenesis

The group of Andres Lopez-Contreras, in collaboration with Ian Hickson´s lab, has published a new study reporting the generation and characterization of a mouse model deficient for PICH. PICH is a protein involved in the resolution of DNA structures called Ultra-Fine Anaphase DNA Bridges (UFBs). These UFBs, which were initially identified by the Hickson lab, are structures which arise between chromosomes during cell division. If UFBs are not resolved before the chromosomes are separated into the daughter cells, this can give rise to genomic instability.

Albers et al. designed and generated a conditional KO mouse model for PICH in collaboration with the Transgenic Unit at the University of Copenhagen. With this conditional KO mouse the researchers are able to delete the gene in specific tissues, and therefore study the function of PICH in each of these tissues, by crossing the mice with specific Cre recombinase mouse models. The new PICH mouse model also makes it possible to study the role of PICH in an entire organism, which makes it easier to understand which functions the protein could have in humans.

In the current article by Albers et al., published in Cell reports, the researchers have demonstrated that the absence of PICH leads to a generalized accumulation of DNA damage across the embryo. This is incompatible with normal development and eventually leads to embryonic lethality. In addition, the study shows that PICH deficient cells are resistant to Ras-induced transformation. Overall, PICH seems to be essential for cells with high proliferation rates, which could have further implications in tumorigenesis. Interestingly, PICH heterozygous females are born at sub-Mendelian ratios, and show fertility alterations. Now, we want to exploit the PICH heterozygous and the PICH conditional KO models to investigate the relevance of PICH in tumorigenesis in an animal model and to gain insights in the mechanisms behind reduced fertility.

Reference:
Albers E, Sbroggiò M, Pladevall-Morera D, Bizard AH, Avram A, Gonzalez P, Martin-Gonzalez J, Hickson ID, Lopez-Contreras AJ. (2018)
Loss of PICH Results in Chromosomal Instability, p53 Activation, and Embryonic Lethality.
Cell Rep. 24(12):3274-3284.