ALYREF condensation stabilizes m(5)C-modified PARP10 mRNA and promotes PI3K-AKT signaling in ovarian cancer.

The role of epigenetic regulation of RNAs in the tumorigenesis remains incompletely understood. This study uncovers a critical function of the 5-methylcytosine (m(5)C) RNA modification reader protein ALYREF (also termed, ALY; BEF) in ovarian cancer. ALYREF is elevated in ovarian cancer patient samples, and its depletion reduces ovarian tumorigenesis and metastasis in mice in a m(5)C-dependent manner. Mechanistically, ALYREF binds to the m(5)C-modified mRNA of ADP-ribosyltransferase PARP10, competing with exosome complex component MTR4, and enhancing the stability and nuclear export of PARP10 mRNA. Further, ALYREF forms condensates in the nucleus of ovarian cancer cells, and depletion or mutation of ALYREF's intrinsically disordered regions rescues its control on PARP10 mRNA nucleoplasmic distribution and stability, reduces tumor growth and is required for promotion of ovarian cancer aggressiveness and proliferation. Finally, ALYREF and PARP10 expression correlate with poor prognosis in ovarian cancer patients. Together, these findings suggest that ALYREF phase separation facilitates the malignant progression of ovarian cancer by promoting PARP10 expression and thereby enhancing PARP10-dependent proliferative pathways in a m(5)C-dependent manner.