TY - UNPB
T1 - RNA Helicase DDX3 Regulates RAD51 Localization and DNA Damage Repair in Ewing Sarcoma
AU - Randolph, Matthew E
AU - Afifi, Marwa
AU - Gorthi, Aparna
AU - Weil, Rachel
AU - Wilky, Breelyn A
AU - Weinreb, Joshua
AU - Ciero, Paul
AU - Ter Hoeve, Natalie
AU - van Diest, Paul J
AU - Raman, Venu
AU - Bishop, Alexander J R
AU - Loeb, David M
PY - 2023/6/10
Y1 - 2023/6/10
N2 - We previously demonstrated that RNA helicase DDX3X (DDX3) can be a therapeutic target in Ewing sarcoma (EWS), but its role in EWS biology remains unclear. The present work demonstrates that DDX3 plays a unique role in DNA damage repair (DDR). We show that DDX3 interacts with several proteins involved in homologous recombination, including RAD51, RECQL1, RPA32, and XRCC2. In particular, DDX3 colocalizes with RAD51 and RNA:DNA hybrid structures in the cytoplasm of EWS cells. Inhibition of DDX3 RNA helicase activity increases cytoplasmic RNA:DNA hybrids, sequestering RAD51 in the cytoplasm, which impairs nuclear translocation of RAD51 to sites of double-stranded DNA breaks thus increasing sensitivity of EWS to radiation treatment, both
in vitro and
in vivo . This discovery lays the foundation for exploring new therapeutic approaches directed at manipulating DDR protein localization in solid tumors.
AB - We previously demonstrated that RNA helicase DDX3X (DDX3) can be a therapeutic target in Ewing sarcoma (EWS), but its role in EWS biology remains unclear. The present work demonstrates that DDX3 plays a unique role in DNA damage repair (DDR). We show that DDX3 interacts with several proteins involved in homologous recombination, including RAD51, RECQL1, RPA32, and XRCC2. In particular, DDX3 colocalizes with RAD51 and RNA:DNA hybrid structures in the cytoplasm of EWS cells. Inhibition of DDX3 RNA helicase activity increases cytoplasmic RNA:DNA hybrids, sequestering RAD51 in the cytoplasm, which impairs nuclear translocation of RAD51 to sites of double-stranded DNA breaks thus increasing sensitivity of EWS to radiation treatment, both
in vitro and
in vivo . This discovery lays the foundation for exploring new therapeutic approaches directed at manipulating DDR protein localization in solid tumors.
U2 - 10.1101/2023.06.10.544474
DO - 10.1101/2023.06.10.544474
M3 - Preprint
C2 - 37333164
SP - 1
EP - 40
BT - RNA Helicase DDX3 Regulates RAD51 Localization and DNA Damage Repair in Ewing Sarcoma
PB - BioRxiv
ER -