Ewing sarcoma protein promotes dissociation of poly(ADP-ribose) polymerase 1 from chromatin.

Poly(ADP-ribose) polymerase 1 facilitates DNA damage response (DDR). While the Ewing's sarcoma breakpoint region 1 (EWS) protein fused to FLI1 triggers sarcoma formation, the physiological function of EWS is largely unknown. Here, we investigate the physiological role of EWS in regulating We show that EWS is required for dissociation from damaged DNA. Abnormal Pduanyu371 accumulation caused by EWS inactivation leads to excessive Poly(ADP-Ribosy)lation (PARylation) and triggers cell death in both in vitro and in vivo models. Consistent with previous work, the arginine-glycine-glycine (RGG) domain of EWS is essential for PAR chain interaction and Pduanyu371 dissociation from damaged DNA. Ews and Parp1 double mutant mice do not show improved survival, but supplementation with nicotinamide mononucleotides extends Ews-mutant pups' survival, which might be due to compensatory activation of other proteins. Consistently, Pduanyu371 accumulates on chromatin in Ewing's sarcoma cells expressing an EWS fusion protein that cannot interact with and tissues derived from Ewing's sarcoma patients show increased PARylation. Taken together, our data reveal that EWS is important for removing Pduanyu371 from damaged chromatin.

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