Enhanced DNA-repair capacity and resistance to chemically induced carcinogenesis upon deletion of the phosphatase regulator NIPP1

Iris Verbinnen,Shannah Boens,Mathieu Bollen,Kathelijne Szekér,Aleyde Van Eynde,Monica Ferreira,Louise Van Wijk

doi:10.1038/s41389-020-0214-3

Abstract

Nuclear Inhibitor of PP1 (NIPP1) is a conserved regulatory subunit of protein phosphatase PP1. The selective deletion of NIPP1 in mouse liver parenchymal cells or skin epidermal cells culminates in a late-onset hyperproliferation of a subset of resident progenitor cells. Although a hyperplastic phenotype is usually tumor promoting, we show here that the absence of NIPP1 conferred a strong resistance to chemically induced hepatocellular or skin carcinoma. The ablation of NIPP1 did not affect the metabolism of the administered mutagens (diethylnitrosamine or 7,12-dimethylbenz[a]anthracene), but reduced the conversion of mutagen-induced covalent DNA modifications into cancer-initiating mutations. This reduced sensitivity to mutagens correlated with an enhanced DNA-damage response and an augmented expression of rate-limiting DNA-repair proteins (MGMT in liver, XPD and XPG in skin), hinting at an increased DNA-repair capacity. Our data identify NIPP1 as a repressor of DNA repair and as a promising target for novel cancer prevention and treatment therapies.

Highlights

Nuclear Inhibitor of PP1 (NIPP1) (38 kDa), encoded by PPP1R8, is a ubiquitously expressed nuclear protein that targets phosphoproteins for regulated dephosphorylation by associated protein Ser/Thr phosphatase PP11–3
We compared the response of CTRs and skin knockout (SKO) with two-stage skin carcinogenesis, as induced by the topical administration of DMBA and/or tumor-promoting phorbol ester 12-Otetradecanoylphorbol-13-acetate (TPA)
This finding was unexpected as the SKO and liver knockout (LKO) models develop a spontaneous hyperproliferation phenotype, which is usually associated with an increased sensitivity to tumorigenesis[30,31]

Summary

Introduction

NIPP1 (38 kDa), encoded by PPP1R8, is a ubiquitously expressed nuclear protein that targets phosphoproteins for regulated dephosphorylation by associated protein Ser/Thr phosphatase PP11–3. Our data demonstrate that the NIPP1 SKOs and LKOs, despite the associated hyperproliferation phenotype, were strongly resistant to induced mutagenesis and carcinogenesis. We compared the response of CTRs and SKOs with two-stage skin carcinogenesis, as induced by the topical administration of DMBA and/or TPA.

Results

Conclusion