Fig. 8.

Par3 directs epidermal fate decisions through coupling Rho/actomyosin contractility to mitotic fidelity. Model. Par3 regulates actomyosin contractility in a Rho-dependent manner. Loss of Par3 alters keratinocyte mechanics resulting in mitotic infidelity and accumulation of DNA damage and p53, which in turn fuels differentiation and disturbs epithelial homeostasis. Restoring myosin activity in Par3-deficient keratinocytes is sufficient to normalize mitosis, and to prevent ectopic DNA damage, premature differentiation, and suprabasal fate. These data establish a role of Par3 in keratinocyte mechanics and mitotic fidelity. Rather than promoting asymmetric/perpendicular mitotic spindle orientation, altered polarity protein function in adult epithelia causes ectopic differentiated fate due to impaired cortical contractility that yields mitosis-related DNA damage and as consequence lower fitness