Polycomb RING1B in neural stem cells proliferation

Abstract

Polycomb protein RING1B is part of the E3 ligase that makes the core component of Polycomb Repressive Complex 1 complexes responsible for monoubiquitination of histone H2A at lysine 119. RING1B has been described as transcriptional repressor and chromatin modifier, indispensable for a proper embryonic development and lineage specification in cellular differentiation. Previous work in our laboratory has revealed additional, non transcriptional functions for RING1B i.e in S-phase progression. Using unperturbed neural stem cells (NSCs) derived from a murine conditional model of loss-of-function of RING1B, we unveil roles of RING1B in cell proliferation, DNA damage and redox homeostasis, independently of its activity as transcriptional repressor. RING1B deficiency caused p21/CDKN1A upregulation, the principal mediator of the proliferative defect. This is mostly due to activation of DNA damage response (DDR). Upregulation of p21 followed the known ATM/P53/p21 DDR axis, as shown by restoration of proliferation rate in p21/Cdkn1a and Tp53 knock out NSCs, or in the presence of ATM inhibitor. Concurrent with proliferation arrest of RING1B-depleted NSCs, accumulation of double-strand breaks (DSBs) originated, at least in part, by an increase in endogenous Reactive Oxygen Species (ROS). Consistently, treatment with antioxidant was able to decrease DNA damage and recover normal proliferation. This essential function, preventing accumulation of ROS in NSCs was fulfilled by RING1B, but not its paralog RING1A through stabilization of Polycomb cofactor BMI-1. In summary, we have identified a novel function of RING1B promoting proliferation of multipotent progenitors through the maintenance of physiological levels of oxidative stress, avoiding and managing a response to DNA damage through mechanisms independent, at least partially, of its better known as transcriptional repressor and instead assuring the stability of its own cofactor in NSCs.