DNA
DNA修复
细胞生物学
DNA损伤
癌症研究
生物
化学
遗传学
作者
Hiro Sato,Atsuko Niimi,Takaaki Yasuhara,Tiara Bunga Mayang Permata,Yoshihiro Hagiwara,Motohide Isono,Endang Nuryadi,Ryota Sekine,Takahiro Oike,Sangeeta Kakoti,Yuya Yoshimoto,Kathryn D. Held,Yoshiyuki Suzuki,Koji Kono,Kiyoshi Miyagawa,Takashi Nakano,Atsushi Shibata
标识
DOI:10.1038/s41467-017-01883-9
摘要
Abstract Accumulating evidence suggests that exogenous cellular stress induces PD-L1 upregulation in cancer. A DNA double-strand break (DSB) is the most critical type of genotoxic stress, but the involvement of DSB repair in PD-L1 expression has not been investigated. Here we show that PD-L1 expression in cancer cells is upregulated in response to DSBs. This upregulation requires ATM/ATR/Chk1 kinases. Using an siRNA library targeting DSB repair genes, we discover that BRCA2 depletion enhances Chk1-dependent PD-L1 upregulation after X-rays or PARP inhibition. In addition, we show that Ku70/80 depletion substantially enhances PD-L1 upregulation after X-rays. The upregulation by Ku80 depletion requires Chk1 activation following DNA end-resection by Exonuclease 1. DSBs activate STAT1 and STAT3 signalling, and IRF1 is required for DSB-dependent PD-L1 upregulation. Thus, our findings reveal the involvement of DSB repair in PD-L1 expression and provide mechanistic insight into how PD-L1 expression is regulated after DSBs.
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