Abstract A090: A novel THO complex member LENG8 connects mRNP export, genome integrity and tumorigenesis

THO/TREX complex is evolutionarily conserved from yeast to human and required for both of mRNP export and genome integrity, but the underlying mechanism remains unknown. Here we demonstrate that DNA damage represses mRNA biogenesis and export, and recruits mRNP to the DNA damage foci. LENG8, an evolutionarily conserved nuclear protein, is a novel member of THO/TREX complex and connects the mRNP machinery with poly(ADP-ribosyl)transferase PARP1. The expression of THOC1 and LENG8 are lower in various human tumors including gastric tumors as well as lung cancers, and their abundancy correlates with poor prognosis of patients. We show that knockdown of THOCs or LENG8 promotes proteolytic cleavage of PARP1, suppresses DNA repair and therefore increases tumor growth both in vitro and in vivo. Our findings suggests THO/TREX complex as a novel regulator of genome integrity and a potential therapeutic target in cancer prevention and treatment.

Citation Format: Nan Zhang, Yongxu Zhao, Jianxia Chen, Qiurong Ding, Feng Liu. A novel THO complex member LENG8 connects mRNP export, genome integrity and tumorigenesis [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A090. doi:10.1158/1535-7163.TARG-19-A090