REXO4 is a 3'-5' exonuclease that functions primarily in R-loop processing and ribosomal RNA metabolism. Its primary mechanism involves collaborating with RNaseH1 to degrade R-loops through an "endo/exo-cleavage coupling" mode, where REXO4 directly degrades RNA strands via its exonuclease activity while stimulating RNaseH1 endonuclease activity 1. REXO4 exhibits cell cycle-dependent subcellular localization, localizing to the nucleolus during interphase through an N-terminal nucleolar localization sequence and to perichromosomal regions of mitotic chr9 2. The protein associates with ribosomal components and is essential for rRNA processing and ribosome biogenesis, as REXO4 depletion causes G1/S cell cycle arrest and reduced viability 2. In disease contexts, REXO4 is overexpressed in human cancers, and REXO4-deficient tumors display elevated R-loop-associated mutation burden 1. REXO4 inhibition increases chemotherapeutic sensitivity to alkylating and G4-stabilizing drugs while activating cGAS-mediated antitumor immunity 1. Additionally, REXO4 variants have been identified in familial prolactinoma and female infertility cases 3, 4, suggesting broader roles in endocrine and reproductive function. REXO4 was also identified as a novel stress granule protein 5.