Open AccessPP1 regulatory subunit NIPP1 regulates transcription of E2F1 target genes following DNA damage
Author(s) -
Hanaki Shunsuke,
Habara Makoto,
Masaki Takahiro,
Maeda Keisuke,
Sato Yuki,
Nakanishi Makoto,
Shimada Midori
Publication year - 2021
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14924
Subject(s) - dephosphorylation , phosphorylation , biology , protein phosphatase 1 , e2f1 , e2f , phosphatase , gene , protein subunit , kinase , microbiology and biotechnology , transcription factor , genetics
DNA damage induces transcriptional repression of E2F1 target genes and a reduction in histone H3‐Thr 11 phosphorylation (H3‐pThr 11 ) at E2F1 target gene promoters. Dephosphorylation of H3‐pThr11 is partly mediated by Chk1 kinase and protein phosphatase 1γ (PP1γ) phosphatase. Here, we isolated NIPP1 as a regulator of PP1γ‐mediated H3‐pThr 11 by surveying nearly 200 PP1 interactor proteins. We found that NIPP1 inhibits PP1γ‐mediated dephosphorylation of H3‐pThr 11 both in vivo and in vitro. By generating NIPP1‐depleted cells, we showed that NIPP1 is required for cell proliferation and the expression of E2F1 target genes. Upon DNA damage, activated protein kinase A (PKA) phosphorylated the NIPP1‐Ser 199 residue, adjacent to the PP1 binding motif (RVxF), and triggered the dissociation of NIPP1 from PP1γ, leading to the activation of PP1γ. Furthermore, the inhibition of PKA activity led to the activation of E2F target genes. Statistical analysis confirmed that the expression of NIPP1 was positively correlated with E2F target genes. Taken together, these findings demonstrate that the PP1 regulatory subunit NIPP1 modulates E2F1 target genes by linking PKA and PP1γ during DNA damage.