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Omics score: 5

Radiotherapy induced sarcoma

ABSTRACT: Whole genome library making will be performed on genomic DNA derived from radiotherapy induced sarcoma samples and matched normal DNA from the same patients. Next Generation sequencing will be performed on the resulting libraries and mapped to build 37 of the human reference genome to facilitate the identification of mutations

PROVIDER: EGAS00001000138 | EGA |

REPOSITORIES: EGA

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Radiotherapy induced Sarcoma exome

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Project description: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.

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