Proteomics

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Ewing sarcoma protein-mediated regulation of poly(ADP-ribose) polymerase 1 dissociation

ABSTRACT: Poly(ADP-ribose) polymerase 1 (PARP1) critically facilitates DNA damage response (DDR) that suppresses genomic instability. However, the physiological function of PARP1 in regulating genomic integrity is unclear. We investigated the Ewing’s sarcoma breakpoint region 1 (EWS) and found that it regulated the physiological function of PARP1. EWS was indispensable to dissociation of PARP1 from damaged DNA, promoting DDR and regulating DDR protein expression. Abnormal PARP1 accumulation due to EWS expression silencing, induced hyper-PARylation, which exhausted cellular NAD+ levels and caused cell death in in vitro and in vivo. Positively charged EWS arginine-glycine-glycine (Arg-Gly-Gly, RGG) domains directly interact with poly ADP-ribose (PAR) chains produced by PARP1 and are essential to dissociate PARP1 from damaged DNA. Consistently, Ewing’s sarcoma cells with defective EWS function accumulated PARP1 on chromatin and tissues from Ewing’s sarcoma patients, exhibiting high PARylation levels. Taken together, loss of EWS causes defects in PARP1 dissociation and results in genomic instability.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: Byung-gyu kim  

LAB HEAD: Kyungjae Myung

PROVIDER: PXD016145 | Pride | 2020-11-03

REPOSITORIES: Pride

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Dataset's files

Source:
Action DRS
MPS_Mix_SILAC_quant_20170411_final.sf3 Other
mix_2fold_re.raw Raw
mix_2fold_rePD2.1.msf Msf
mix_2fold_rePD2.1.msf.mzid_mix_2fold_rePD2.1.msf.MGF Mzid
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Publications

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

Lee Seon-Gyeong SG   Kim Namwoo N   Kim Su-Min SM   Park In Bae IB   Kim Hyejin H   Kim Shinseog S   Kim Byung-Gyu BG   Hwang Jung Me JM   Baek In-Joon IJ   Gartner Anton A   Park Jun Hong JH   Myung Kyungjae K  

EMBO reports 20201001 11

Poly(ADP-ribose) polymerase 1 (PARP1) 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 PARP1. We show that EWS is required for PARP1 dissociation from damaged DNA. Abnormal PARP1 accumulation caused by EWS inactivation leads to excessive Poly(ADP-Ribosy)lation (PARylation) and triggers ce  ...[more]

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