TUG1-mediated R-loop resolution at microsatellite loci as a prerequisite for cancer cell proliferation
Miho Suzuki, Kenta Iijima, Koichi Ogami, Keiko Shinjo, Yoshiteru Murofushi, Jingqi Xie, Xuebing Wang, Yotaro Kitano, A. Mamiya, Yuji Kibe, Tatsunori Nishimura, Fumiharu Ohka, Ryuta Saito, Shinya Sato, Junya Kobayashi, Ryoji Yao, Kanjiro Miyata, Kazunori Kataoka, Hiroshi Suzuki, Yutaka Kondo
Abstract
Oncogene-induced DNA replication stress (RS) and consequent pathogenic R-loop formation are known to impede S phase progression. Nonetheless, cancer cells continuously proliferate under such high-stressed conditions through incompletely understood mechanisms. Here, we report taurine upregulated gene 1 (TUG1) long noncoding RNA (lncRNA), which is highly expressed in many types of cancers, as an important regulator of intrinsic R-loop in cancer cells. Under RS conditions, TUG1 is rapidly upregulated via activation of the ATR-CHK1 signaling pathway, interacts with RPA and DHX9, and engages in resolving R-loops at certain loci, particularly at the CA repeat microsatellite loci. Depletion of TUG1 leads to overabundant R-loops and enhanced RS, leading to substantial inhibition of tumor growth. Our data reveal a role of TUG1 as molecule important for resolving R-loop accumulation in cancer cells and suggest targeting TUG1 as a potent therapeutic approach for cancer treatment.