E2F-Family Members Engage the PIDDosome to Limit Hepatocyte Ploidy in Liver Development and Regeneration

Abstract

Highlights d The PIDDosome controls hepatocyte ploidy during postnatal development & regeneration d The PIDDosome defines the speed of liver regeneration posthepatectomy d Aneuploidy in the liver correlates with basal ploidy state but is not limited by CASP2 d E2F family members regulate expression of CASP2 and PIDD1 for liver ploidy control

PIDDosome-induced p53-activation for ploidy restriction facilitates hepatocarcinogenesis

“…Loss of either PIDDosome component drastically increases hepatocyte ploidy. While liver function seems unaffected, the degree of aneuploidy is relatively higher as this is linked to the basal ploidy state, but not limited by PIDDosome-induced p53 function itself (Sladky et al, 2020).…”

“…Liver cells are largely polyploid, a feature usually linked to chromosomal instability and subsequent aneuploidy, a phenomenon seen to some degree already in healthy hepatocytes (Knouse et al, 2014;Sladky et al, 2020). In most other cell types, polyploidy and chromosomal instability are considered to put cells at risk for malignant transformation (Ganem et al, 2007;Lens and Medema, 2019).…”

“…We recently showed that the PIDDosome controls physiological polyploidization in the liver (Sladky et al, 2020). Hepatocytes utilize this multi-protein complex to control the upper limit of liver ploidy during development and regeneration (Sladky et al, 2020).…”

“…We recently showed that the PIDDosome controls physiological polyploidization in the liver (Sladky et al, 2020). Hepatocytes utilize this multi-protein complex to control the upper limit of liver ploidy during development and regeneration (Sladky et al, 2020). In the liver, expression of the centrosome-sensing component PIDD1 and the executioner component caspase-2 is coupled to proliferation, as it is controlled by antagonizing members of the E2F transcription factor family, known for their essential role in ploidy control (Chen et al, 2012;Conner et al, 2003;Pandit et al, 2012).…”

“…The activating transcription factor E2F1 induces PIDD1 and CASP2 expression which allows induction of the PIDDosome-p53-p21 axis to restrict further proliferation of polyploid hepatocytes. This is counteracted by E2F7 and E2F8 repressing PIDDosome transcription to allow for proliferation in a polyploid state in the presence of extra centrosomes (Sladky et al, 2020). Loss of either PIDDosome component drastically increases hepatocyte ploidy.…”