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bioRxiv · 10.1101/2025.02.19.639064

PP4Psy2 regulates Rrm3 and Pif1 helicases to facilitate DSB resection across tandem retrotransposons

Campos, A.·Pulido, L.·Iglesias, L.·Delgado, C.·Sanchez, M.·Villoria, M. T.·Clemente-Blanco, A.
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Abstract

Double-strand break repair is a tightly regulated process that relies on the coordinated activity of kinase and phosphatase complexes. Here we show that the PP4 phosphatase regulatory subunits, Psy2 and Psy4, act as positive and negative regulators of the holoenzyme during DSB repair. Cdk-dependent phosphorylation of Psy2 is crucial for DSB repair but is not required for DNA damage checkpoint inactivation. Lack of Psy2 leads to an asymmetric resection defect on one side of the DSB, a defect that is alleviated by expressing a phosphodeficient H2A variant or by depleting the checkpoint adaptor Rad9. This resection asymmetry is associated to the presence of tandem retrotransposons proximal to the DSB site, underlining the role of PP4Psy2 in stimulating resection across repetitive heterochromatic regions. PP4Psy2 support resection progression through paired transposable elements by reducing the phosphorylation state of Pif1 and Rrm3 helicases during the DSB response. These findings provide a comprehensive framework for the role of PP4Psy2 in resection-mediated DSB repair, highlighting its function in coordinating helicases activity to preserve genomic stability in response to DNA damage.

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Campos, A., Pulido, L., Iglesias, L., Delgado, C., Sanchez, M., Villoria, M. T., Clemente-Blanco, A.. 2025-02-26. PP4Psy2 regulates Rrm3 and Pif1 helicases to facilitate DSB resection across tandem retrotransposons. https://doi.org/10.1101/2025.02.19.639064

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