Nuclear localization of the glutaminyl-tRNA synthetase QARS reveals its role in DNA damage response in ovarian cancer.

Uncovering novel mechanisms controlling DNA damage response (DDR) is essential to better understand the molecular features of high-grade serous ovarian cancers (HGSOC), which remain a clinical challenge. Here, we demonstrate that the glutaminyl-tRNA-synthetase QARS is a key player in DDR. We show that QARS is regulated at translational level by the MAPK pathway in HGSOC and controls homologous recombination (HR) through a translation-independent mechanism. Analyses combining RNA sequencing, immunohistochemistry, proteomic data and functional assays from HGSOC patient cohorts and relevant cellular models reveal that QARS promotes DNA repair via the HR pathway. Interestingly, we uncover that QARS is located in the nucleus and is enriched at chromatin upon DNA damage. Nuclear QARS controls HR by interacting with the nuclear autoantigen SP100, a major component of PML-nuclear bodies (PML-NB), that are regulatory hubs for DNA repair proteins. Our data highlight nuclear functions and mechanisms for QARS involving SP100, PML-NB and MRE11 that enhance HR in HGSOC.