CDK2 and PKA mediated-sequential phosphorylation is critical for p19INK4d function in the DNA damage response.

DNA damage triggers a phosphorylation-based signaling cascade known as the DNA damage response. p19INK4d, a member of the INK4 family of CDK4/6 inhibitors, has been reported to participate in the DNA damage response promoting DNA repair and cell survival. Here, we provide mechanistic insight into th...

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Autores principales:	Mariela C Marazita, M Florencia Ogara, Silvina V Sonzogni, Marcelo Martí, Nelson J Dusetti, Omar P Pignataro, Eduardo T Cánepa
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0e595ffbe060447981e7bb57d4477c2d
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spelling	oai:doaj.org-article:0e595ffbe060447981e7bb57d4477c2d2021-11-18T07:20:57ZCDK2 and PKA mediated-sequential phosphorylation is critical for p19INK4d function in the DNA damage response.1932-620310.1371/journal.pone.0035638https://doaj.org/article/0e595ffbe060447981e7bb57d4477c2d2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22558186/?tool=EBIhttps://doaj.org/toc/1932-6203DNA damage triggers a phosphorylation-based signaling cascade known as the DNA damage response. p19INK4d, a member of the INK4 family of CDK4/6 inhibitors, has been reported to participate in the DNA damage response promoting DNA repair and cell survival. Here, we provide mechanistic insight into the activation mechanism of p19INK4d linked to the response to DNA damage. Results showed that p19INK4d becomes phosphorylated following UV radiation, β-amyloid peptide and cisplatin treatments. ATM-Chk2/ATR-Chk1 signaling pathways were found to be differentially involved in p19INK4d phosphorylation depending on the type of DNA damage. Two sequential phosphorylation events at serine 76 and threonine 141 were identified using p19INK4d single-point mutants in metabolic labeling assays with (32)P-orthophosphate. CDK2 and PKA were found to participate in p19INK4d phosphorylation process and that they would mediate serine 76 and threonine 141 modifications respectively. Nuclear translocation of p19INK4d induced by DNA damage was shown to be dependent on serine 76 phosphorylation. Most importantly, both phosphorylation sites were found to be crucial for p19INK4d function in DNA repair and cell survival. In contrast, serine 76 and threonine 141 were dispensable for CDK4/6 inhibition highlighting the independence of p19INK4d functions, in agreement with our previous findings. These results constitute the first description of the activation mechanism of p19INK4d in response to genotoxic stress and demonstrate the functional relevance of this activation following DNA damage.Mariela C MarazitaM Florencia OgaraSilvina V SonzogniMarcelo MartíNelson J DusettiOmar P PignataroEduardo T CánepaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 4, p e35638 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mariela C Marazita M Florencia Ogara Silvina V Sonzogni Marcelo Martí Nelson J Dusetti Omar P Pignataro Eduardo T Cánepa CDK2 and PKA mediated-sequential phosphorylation is critical for p19INK4d function in the DNA damage response.
description	DNA damage triggers a phosphorylation-based signaling cascade known as the DNA damage response. p19INK4d, a member of the INK4 family of CDK4/6 inhibitors, has been reported to participate in the DNA damage response promoting DNA repair and cell survival. Here, we provide mechanistic insight into the activation mechanism of p19INK4d linked to the response to DNA damage. Results showed that p19INK4d becomes phosphorylated following UV radiation, β-amyloid peptide and cisplatin treatments. ATM-Chk2/ATR-Chk1 signaling pathways were found to be differentially involved in p19INK4d phosphorylation depending on the type of DNA damage. Two sequential phosphorylation events at serine 76 and threonine 141 were identified using p19INK4d single-point mutants in metabolic labeling assays with (32)P-orthophosphate. CDK2 and PKA were found to participate in p19INK4d phosphorylation process and that they would mediate serine 76 and threonine 141 modifications respectively. Nuclear translocation of p19INK4d induced by DNA damage was shown to be dependent on serine 76 phosphorylation. Most importantly, both phosphorylation sites were found to be crucial for p19INK4d function in DNA repair and cell survival. In contrast, serine 76 and threonine 141 were dispensable for CDK4/6 inhibition highlighting the independence of p19INK4d functions, in agreement with our previous findings. These results constitute the first description of the activation mechanism of p19INK4d in response to genotoxic stress and demonstrate the functional relevance of this activation following DNA damage.
format	article
author	Mariela C Marazita M Florencia Ogara Silvina V Sonzogni Marcelo Martí Nelson J Dusetti Omar P Pignataro Eduardo T Cánepa
author_facet	Mariela C Marazita M Florencia Ogara Silvina V Sonzogni Marcelo Martí Nelson J Dusetti Omar P Pignataro Eduardo T Cánepa
author_sort	Mariela C Marazita
title	CDK2 and PKA mediated-sequential phosphorylation is critical for p19INK4d function in the DNA damage response.
title_short	CDK2 and PKA mediated-sequential phosphorylation is critical for p19INK4d function in the DNA damage response.
title_full	CDK2 and PKA mediated-sequential phosphorylation is critical for p19INK4d function in the DNA damage response.
title_fullStr	CDK2 and PKA mediated-sequential phosphorylation is critical for p19INK4d function in the DNA damage response.
title_full_unstemmed	CDK2 and PKA mediated-sequential phosphorylation is critical for p19INK4d function in the DNA damage response.
title_sort	cdk2 and pka mediated-sequential phosphorylation is critical for p19ink4d function in the dna damage response.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/0e595ffbe060447981e7bb57d4477c2d
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CDK2 and PKA mediated-sequential phosphorylation is critical for p19INK4d function in the DNA damage response.

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