# Pervasive phenotypic effects of FBXO42 are promoted by regulation of PP4 phosphatase

## TL;DR

This study reveals that FBXO42 regulates PP4 phosphatase activity, which is crucial for DNA damage signaling and genome stability.

## Contribution

FBXO42 is identified as a novel regulator of PP4 phosphatase through ubiquitination, impacting DNA damage response and genome stability.

## Key findings

- FBXO42 ubiquitinates the PP4 complex to control its activity and subunit assembly.
- Loss of FBXO42 increases PP4 activity, leading to disrupted DNA damage signaling and genome instability.
- Cells without FBXO42 show heightened sensitivity to ionizing radiation due to elevated PP4 activity.

## Abstract

F-box proteins are the substrate recognition modules of the SCF (SKP1–Cullin–F-box) E3 ubiquitin ligase complex. FBXO42, an understudied member of this family, has recently emerged as a modulator of key cellular processes, including cell cycle progression, the DNA damage response, and glioma stem cell survival. In this study, we define the function of FBXO42 as a major regulator of the protein phosphatase PP4. Phosphoprotein phosphatases (PPPs) have a broad array of substrates, hence necessitating tight regulation. We observe that FBXO42 ubiquitinates the PP4 complex to govern the assembly of regulatory and catalytic subunits, with the net effect of restraining the latter’s phosphatase activity. FBXO42 depletion unleashes PP4 activity, with broad cellular effects, highlighting FBXO42 as a novel regulatory node in ubiquitin-mediated signalling for future therapeutic exploitation.

The F-box protein ubiquitin ligase adaptor FBXO42 has been implicated in various key cellular processes. This work shows that FBXO42 limits PP4 phosphatase activity to ensure proper DNA damage signalling, with its loss disrupting phosphorylation dynamics and compromising genome stability.

FBXO42 binds the PP4 phosphatase holoenzyme.FBXO42 loss promotes widespread phosphorylation changes reflecting increased PP4 activity.FBXO42 loss promotes unscheduled dephosphorylation of DNA damage response substrates through increased PP4 activity (PP4R2).Cells lacking FBXO42 exhibit increased sensitivity to ionising radiation, dependent on increased PP4C/PP4R2 activity.

FBXO42 binds the PP4 phosphatase holoenzyme.

FBXO42 loss promotes widespread phosphorylation changes reflecting increased PP4 activity.

FBXO42 loss promotes unscheduled dephosphorylation of DNA damage response substrates through increased PP4 activity (PP4R2).

Cells lacking FBXO42 exhibit increased sensitivity to ionising radiation, dependent on increased PP4C/PP4R2 activity.

The ubiquitin ligase adaptor FBXO42 limits PP4 phosphatase activity to ensure proper DNA damage signalling.