Heterozygous loss‐of‐function alleles associate the conserved 3′‐5′ exoribonuclease EXOSC10 with hypersensitivity to the anticancer drug 5‐fluorouracil

The 3′‐5′ exoribonuclease EXOSC10 degrades aberrant mRNAs and noncoding RNAs in cooperation with the nuclear RNA exosome. EXOSC10's localization and stability are regulated by sumoylation and proteasomal degradation in response to stress, and the protein is essential for cell growth and proliferation, fertility, hematopoiesis, and brain development. EXOSC10 is a cancer biomarker; its activity is inhibited by the widely used anticancer drug 5‐fluorouracil (5‐FU) and the protein's depletion sensitizes cells to 5‐FU. We employed mass spectrometry to reveal EXOSC10's post‐translational modifications, such as phosphorylation, acetylation and ubiquitination, and to explore its protein interaction network, which includes RNA exosome subunits and enzymes involved in protein degradation. Furthermore, we find that the EXOSC10 S402T allele identified in colon cancer and located within a motif for targeted proteolysis is stable, nuclear but nonfunctional in vivo , since homozygous Exosc10 S402T mice exhibit early embryonic lethality. We identified equivalent S402P/S402A variants and heterozygous loss‐of‐function (LoF) alleles in cancers and healthy individuals using public genomics data. Our findings suggest that recessive EXOSC10 LoF alleles may cause increased 5‐FU sensitivity in tumors bearing de novo mutations and hypertoxicity in heterozygous carriers.