Aquarius RNA helicase Protects Pluripotent Stem Cell Identity

Lalonde, M.; Marquez-Gomez, E.; Lee, C. S. K.; Burton, A.; Tsirkas, I.; Rezende Pabst, F.; Werner, M.; Sajid, A.; Chaves Murriello, A.; Karypidou, X.; Ettinger, A.; Schauer, T.; Straub, T.; Torres-Padilla, M.-E.; Scialdone, A.; Hamperl, S.

doi:10.64898/2026.04.24.720612

bioRxiv · 10.64898/2026.04.24.720612

Aquarius RNA helicase Protects Pluripotent Stem Cell Identity

Lalonde, M.·Marquez-Gomez, E.·Lee, C. S. K.·Burton, A.·Tsirkas, I.·Rezende Pabst, F.·Werner, M.·Sajid, A.·Chaves Murriello, A.·Karypidou, X.·Ettinger, A.·Schauer, T.·Straub, T.·Torres-Padilla, M.-E.·Scialdone, A.·Hamperl, S.

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Abstract

Pluripotent stem cells must reconcile rapid replication with a highly dynamic transcriptional program, creating an inherent susceptibility to transcription-replication conflicts (TRCs). We demonstrate that embryonic stem cells (ESCs) operate in a "resilient" replication mode, tolerating high genomic traffic through the constitutive upregulation of R-loop and TRC resolution pathways. Through a targeted functional screen, we identify the RNA helicase Aquarius (AQR) as an essential safeguard of this state. AQR depletion downregulates these resolution factors, collapsing this stress-resistant program and driving ESCs into unstable, heterogenous states, marked by increased transcriptional entropy and cell-to-cell noise. Mechanistically, we show that key identity-defining genes are preferentially located within R-loop and TRC prone regions, making them uniquely vulnerable to AQR depletion. Our findings establish AQR as a critical governor of transcriptional fidelity, demonstrating that genomic resilience is fundamental to maintaining pluripotent cell identity.

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Lalonde, M., Marquez-Gomez, E., Lee, C. S. K., Burton, A., Tsirkas, I., Rezende Pabst, F., Werner, M., Sajid, A., Chaves Murriello, A., Karypidou, X., Ettinger, A., Schauer, T., Straub, T., Torres-Padilla, M.-E., Scialdone, A., Hamperl, S.. 2026-04-27. Aquarius RNA helicase Protects Pluripotent Stem Cell Identity. https://doi.org/10.64898/2026.04.24.720612

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