# ALYREF condensation stabilizes m5C-modified PARP10 mRNA and promotes PI3K-AKT signaling in ovarian cancer

## TL;DR

A protein called ALYREF helps ovarian cancer grow by protecting a specific RNA modification, leading to increased cancer spread and poor patient outcomes.

## Contribution

This study reveals a new role for ALYREF in ovarian cancer through phase separation and m5C RNA modification.

## Key findings

- ALYREF stabilizes and promotes the nuclear export of PARP10 mRNA in ovarian cancer cells.
- ALYREF forms condensates that are essential for its tumor-promoting function.
- High ALYREF levels correlate with poor prognosis in ovarian cancer patients.

## Abstract

The role of epigenetic regulation of RNAs in the tumorigenesis remains incompletely understood. This study uncovers a critical function of the 5-methylcytosine (m5C) 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 m5C-dependent manner. Mechanistically, ALYREF binds to the m5C-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 m5C-dependent manner.

The interplay between RNA modifications and biomolecular condensates plays an important role in malignancies. This study uncovers a phase separation-dependent role of 5-methylcytosine (m5C) mRNA modification reader ALYREF (aka ALY, BEF) in promoting ovarian cancer.

ALYREF is amplified in ovarian cancer and predicts poor survival.ALYREF facilitates ovarian tumorigenesis and metastasis in mice in a m5C recognition-dependent manner.ALYREF stabilizes m5C-modified mRNA of ADP-ribosyltransferase PARP10, protecting it from exosome complex-dependent degradation.ALYREF forms condensates, which are required for its function in mRNA stability and tumorigenesis.

ALYREF is amplified in ovarian cancer and predicts poor survival.

ALYREF facilitates ovarian tumorigenesis and metastasis in mice in a m5C recognition-dependent manner.

ALYREF stabilizes m5C-modified mRNA of ADP-ribosyltransferase PARP10, protecting it from exosome complex-dependent degradation.

ALYREF forms condensates, which are required for its function in mRNA stability and tumorigenesis.

The 5-methylcytosine reader ALYREF spurs epithelial cancer aggressiveness in phase separation-dependent manner.