Enhanced DNA-repair capacity and resistance to chemically induced carcinogenesis upon deletion of the phosphatase regulator NIPP1
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 phen...
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| Veröffentlicht in: | Oncogenesis (New York, NY) NY), 2020-03, Vol.9 (3), p.30, Article 30 |
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| creator | Verbinnen, Iris Boens, Shannah Ferreira, Monica Szekér, Kathelijne Van Wijk, Louise Van Eynde, Aleyde Bollen, Mathieu |
| description | 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. |
| doi_str_mv | 10.1038/s41389-020-0214-3 |
| format | Article |
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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.</description><identifier>ISSN: 2157-9024</identifier><identifier>EISSN: 2157-9024</identifier><identifier>DOI: 10.1038/s41389-020-0214-3</identifier><identifier>PMID: 32123159</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/51 ; 13/89 ; 631/67/70 ; 631/80 ; 64/60 ; 9,10-Dimethyl-1,2-benzanthracene ; Anthracene ; Apoptosis ; Brief Communication ; Carcinogenesis ; Cell Biology ; Clonal deletion ; Deoxyribonucleic acid ; Diethylnitrosamine ; DNA ; DNA damage ; DNA repair ; Hepatocytes ; Human Genetics ; Internal Medicine ; Medicine ; Medicine & Public Health ; Mutagens ; O6-methylguanine-DNA methyltransferase ; Oncology ; Phenotypes ; Phosphatase ; Progenitor cells ; Protein phosphatase ; Skin cancer ; Skin carcinoma ; Stem cells ; XPD protein</subject><ispartof>Oncogenesis (New York, NY), 2020-03, Vol.9 (3), p.30, Article 30</ispartof><rights>The Author(s) 2020</rights><rights>This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). 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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. 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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. 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| subjects | 13/1 13/51 13/89 631/67/70 631/80 64/60 9,10-Dimethyl-1,2-benzanthracene Anthracene Apoptosis Brief Communication Carcinogenesis Cell Biology Clonal deletion Deoxyribonucleic acid Diethylnitrosamine DNA DNA damage DNA repair Hepatocytes Human Genetics Internal Medicine Medicine Medicine & Public Health Mutagens O6-methylguanine-DNA methyltransferase Oncology Phenotypes Phosphatase Progenitor cells Protein phosphatase Skin cancer Skin carcinoma Stem cells XPD protein |
| title | Enhanced DNA-repair capacity and resistance to chemically induced carcinogenesis upon deletion of the phosphatase regulator NIPP1 |
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