O-GlcNAcylation of the intellectual disability protein DDX3X exerts proteostatic cell cycle control

Conor W.  Mitchell; Huijie Yuan; Andrew T. Ferenbach; Marie Sønderstrup-Jensen; Daan van Aalten

doi:10.1098/rsob.250064

O-GlcNAcylation of the intellectual disability protein DDX3X exerts proteostatic cell cycle control

Conor W. Mitchell
, Huijie Yuan
, Andrew T. Ferenbach
, Marie Sønderstrup-Jensen
, Daan van Aalten (Lead / Corresponding author)

Molecular Cell and Developmental Biology

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

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Abstract

O-GlcNAcylation of intracellular proteins is a key regulator of diverse cellular and developmental processes. Previous studies have demonstrated the acute sensitivity of cell cycle progression to chemical and genetic manipulation of O-GlcNAc homeostasis. However, the mechanisms by which O-GlcNAc regulates the cell cycle remain poorly understood. Here, we report Ser584 O-GlcNAcylation of the RNA helicase DDX3X, a microcephaly-associated protein, as a proteostatic mechanism regulating S-phase entry. Loss of Ser584 O-GlcNAcylation promoted degradation of DDX3X by the proteasome, resulting in reduced expression of the DDX3X target gene cyclin E1 and impaired cell cycle progression from G1 to S phase. These findings display how a single O-GlcNAc site affects DDX3X stability and thereby the cell cycle.

Original language	English
Article number	250064
Number of pages	13
Journal	Open Biology
Volume	15
Issue number	7
Early online date	2 Jul 2025
DOIs	https://doi.org/10.1098/rsob.250064
Publication status	Published - Jul 2025

Keywords

O-GlcNAc
cell cycle
cell signalling

ASJC Scopus subject areas

General Neuroscience
Immunology
General Biochemistry,Genetics and Molecular Biology

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10.1098/rsob.250064Licence: CC BY

Final published versionFinal published version, 4.24 MBLicence: CC BY

Cite this

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title = "O-GlcNAcylation of the intellectual disability protein DDX3X exerts proteostatic cell cycle control",

abstract = "O-GlcNAcylation of intracellular proteins is a key regulator of diverse cellular and developmental processes. Previous studies have demonstrated the acute sensitivity of cell cycle progression to chemical and genetic manipulation of O-GlcNAc homeostasis. However, the mechanisms by which O-GlcNAc regulates the cell cycle remain poorly understood. Here, we report Ser584 O-GlcNAcylation of the RNA helicase DDX3X, a microcephaly-associated protein, as a proteostatic mechanism regulating S-phase entry. Loss of Ser584 O-GlcNAcylation promoted degradation of DDX3X by the proteasome, resulting in reduced expression of the DDX3X target gene cyclin E1 and impaired cell cycle progression from G1 to S phase. These findings display how a single O-GlcNAc site affects DDX3X stability and thereby the cell cycle. ",

keywords = "O-GlcNAc, cell cycle, cell signalling",

author = "Mitchell, \{Conor W.\} and Huijie Yuan and Ferenbach, \{Andrew T.\} and Marie S{\o}nderstrup-Jensen and \{van Aalten\}, Daan",

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year = "2025",

month = jul,

doi = "10.1098/rsob.250064",

language = "English",

volume = "15",

journal = "Open Biology",

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T1 - O-GlcNAcylation of the intellectual disability protein DDX3X exerts proteostatic cell cycle control

AU - Mitchell, Conor W.

AU - Yuan, Huijie

AU - Ferenbach, Andrew T.

AU - Sønderstrup-Jensen, Marie

AU - van Aalten, Daan

PY - 2025/7

Y1 - 2025/7

N2 - O-GlcNAcylation of intracellular proteins is a key regulator of diverse cellular and developmental processes. Previous studies have demonstrated the acute sensitivity of cell cycle progression to chemical and genetic manipulation of O-GlcNAc homeostasis. However, the mechanisms by which O-GlcNAc regulates the cell cycle remain poorly understood. Here, we report Ser584 O-GlcNAcylation of the RNA helicase DDX3X, a microcephaly-associated protein, as a proteostatic mechanism regulating S-phase entry. Loss of Ser584 O-GlcNAcylation promoted degradation of DDX3X by the proteasome, resulting in reduced expression of the DDX3X target gene cyclin E1 and impaired cell cycle progression from G1 to S phase. These findings display how a single O-GlcNAc site affects DDX3X stability and thereby the cell cycle.

AB - O-GlcNAcylation of intracellular proteins is a key regulator of diverse cellular and developmental processes. Previous studies have demonstrated the acute sensitivity of cell cycle progression to chemical and genetic manipulation of O-GlcNAc homeostasis. However, the mechanisms by which O-GlcNAc regulates the cell cycle remain poorly understood. Here, we report Ser584 O-GlcNAcylation of the RNA helicase DDX3X, a microcephaly-associated protein, as a proteostatic mechanism regulating S-phase entry. Loss of Ser584 O-GlcNAcylation promoted degradation of DDX3X by the proteasome, resulting in reduced expression of the DDX3X target gene cyclin E1 and impaired cell cycle progression from G1 to S phase. These findings display how a single O-GlcNAc site affects DDX3X stability and thereby the cell cycle.

KW - O-GlcNAc

KW - cell cycle

KW - cell signalling

UR - https://www.scopus.com/pages/publications/105009971738

U2 - 10.1098/rsob.250064

DO - 10.1098/rsob.250064

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JO - Open Biology

JF - Open Biology

IS - 7

M1 - 250064

ER -

O-GlcNAcylation of the intellectual disability protein DDX3X exerts proteostatic cell cycle control

Abstract

Keywords

ASJC Scopus subject areas

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Molecular Mechanisms of O-GICNAC Signalling (Investigator award)

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O-GlcNAcylation of the intellectual disability protein DDX3X exerts proteostatic cell cycle control

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

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Molecular Mechanisms of O-GICNAC Signalling (Investigator award)

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