Cell cycle dependent regulation of mRNA export in response to replication stress

Abstract

Nuclear export of mRNA is extensively coupled to transcription and processing of mRNA. How mRNA export is mechanistically regulated remains poorly understood. Here, we uncover a physical checkpoint at nuclear speckles that regulates mRNA export during DNA replication in S-phase of the cell cycle. Unbiased screening approaches identify WEE1 and CHK1 as novel mRNA export regulators. mRNA export complexes are recruited to sites of replication stress in S-phase. WEE1 inhibition prematurely activates CDK1 and PLK1, leading to accumulation of R-loop associated mRNA in large nuclear speckles, with late markers of replication stress present around their periphery. This recruitment is dependent on CDK1 activity. Phosphorylation of ALYREF by CDK1 and PLK1 regulates nuclear speckle accumulation of mRNA following replication stress. mRNA export factors including ALYREF are subsequently mis-localised from these speckles, preventing nuclear export of R-loop associated mRNA. Thus, WEE1, CDK1 and PLK1 enforce a cell cycle regulated checkpoint at nuclear speckles that serves to protect the cell from major sources of genome instability by ensuring that R-loop associated mature mRNA is not exported to the cytoplasm.

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BibTeX RIS

BibTeX

@misc{williams2026cell,
  title = {{Cell cycle dependent regulation of mRNA export in response to replication stress}},
  author = {T. Williams and K. Carey and W. Hamilton and L. Ngo and S. van Twest and V. Murphy and J. Lou and A. Das and E. Deeb and C.-S. Ang and I. Nikolic and K. Cowley and K. Simpson and K. Brown and E. Hinde and S. Humphrey and A. Deans and V. Wickramasinghe},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.06.749765},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.06.749765v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - Cell cycle dependent regulation of mRNA export in response to replication stress
AU  - T. Williams
AU  - K. Carey
AU  - W. Hamilton
AU  - L. Ngo
AU  - S. van Twest
AU  - V. Murphy
AU  - J. Lou
AU  - A. Das
AU  - E. Deeb
AU  - C.-S. Ang
AU  - I. Nikolic
AU  - K. Cowley
AU  - K. Simpson
AU  - K. Brown
AU  - E. Hinde
AU  - S. Humphrey
AU  - A. Deans
AU  - V. Wickramasinghe
PY  - 2026
DA  - 2026/09/06
PB  - bioRxiv
DO  - 10.64898/2026.09.06.749765
UR  - https://www.biorxiv.org/content/10.64898/2026.09.06.749765v1
AB  - Nuclear export of mRNA is extensively coupled to transcription and processing of mRNA. How mRNA export is mechanistically regulated remains poorly understood. Here, we uncover a physical checkpoint at nuclear speckles that regulates mRNA export during DNA replication in S-phase of the cell cycle. Unbiased screening approaches identify WEE1 and CHK1 as novel mRNA export regulators. mRNA export complexes are recruited to sites of replication stress in S-phase. WEE1 inhibition prematurely activates CDK1 and PLK1, leading to accumulation of R-loop associated mRNA in large nuclear speckles, with late markers of replication stress present around their periphery. This recruitment is dependent on CDK1 activity. Phosphorylation of ALYREF by CDK1 and PLK1 regulates nuclear speckle accumulation of mRNA following replication stress. mRNA export factors including ALYREF are subsequently mis-localised from these speckles, preventing nuclear export of R-loop associated mRNA. Thus, WEE1, CDK1 and PLK1 enforce a cell cycle regulated checkpoint at nuclear speckles that serves to protect the cell from major sources of genome instability by ensuring that R-loop associated mature mRNA is not exported to the cytoplasm.
ER  -

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