Protein phosphatases from the PPP-type family, such as protein Ser/Thr phosphatase 1 (PP1), are responsible for a plethora of protein dephosphorylation events. The substrate specificity or activity of PP1 is regulated through its interaction with a multitude of proteins. Nuclear inhibitor of PP1 (NIPP1) is both an inhibitor and activator of PP1 and has been associated with several cellular functions. In order to avoid phenotypes after NIPP1 overexpression that are linked to a global cellular effect of PP1 titration from its interactors, Mathieu Bollen and co-workers engineered a cell line that stably expresses a fusion protein of PP1 and NIPP1 (Winkler et al., 2018). The authors show that expression of this PP1–NIPP1 fusion causes slower replication fork progression and induces the formation of RNA–DNA hybrids called R-loops. In addition, these cell lines accumulate DNA double-strand breaks (DSBs), as the repair capacity for DSBs is reduced in the presence of PP1–NIPP1. In accordance with these results, the authors find that the expression of proteins that are needed for DNA damage signalling and repair is diminished. Taken together, this study demonstrates a key role for PP1–NIPP1 in the dephosphorylation of substrates that control the DNA damage response. Furthermore, it establishes a new strategy to dissect the biological functions of PP1-interacting regulatory proteins.
