DNA damage-induced nuclear translocation of Apaf-1 is mediated by nucleoporin Nup107 |
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Authors: | Léonard Jagot-Lacoussiere Audrey Faye Heriberto Bruzzoni-Giovanelli Bruno O Villoutreix Jean-Christophe Rain Jean-Luc Poyet |
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Affiliation: | 1.INSERM UMRS1160; Université Denis Diderot; Institut Universitaire d''Hématologie; Hôpital Saint-Louis; Paris, France;2.c-Dithem; Inserm Consortium for Discovery and Innovation; Paris, France;3.INSERM UMRS 973; Université Paris Diderot; Sorbonne Paris Cité; Paris, France;4.Hybrigenics; Paris, France |
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Abstract: | Beside its central role in the mitochondria-dependent cell death pathway, the apoptotic protease activating factor 1 (Apaf-1) is involved in the DNA damage response through cell-cycle arrest induced by genotoxic stress. This non-apoptotic function requires a nuclear translocation of Apaf-1 during the G1-to-S transition. However, the mechanisms that trigger the nuclear accumulation of Apaf-1 upon DNA damage remain to be investigated. Here we show that the main 4 isoforms of Apaf-1 can undergo nuclear translocation and restore Apaf-1 deficient MEFs cell cycle arrest in the S phase following genotoxic stress through activation of Chk-1. Interestingly, DNA damage-dependent nuclear accumulation of Apaf-1 occurs independently of p53 and the retinoblastoma (pRb) pathway. We demonstrated that Apaf-1 associates with the nucleoporin Nup107 and this association is necessary for Apaf-1 nuclear import. The CED-4 domain of Apaf-1 directly binds to the central domain of Nup107 in an ATR-regulated, phosphorylation-dependent manner. Interestingly, expression of the Apaf-1-interacting domain of Nup107 interfered with Apaf-1 nuclear translocation upon genotoxic stress, resulting in a marked reduction of Chk-1 activation and cell cycle arrest. Thus, our results confirm the crucial role of Apaf-1 nuclear relocalization in mediating cell-cycle arrest induced by genotoxic stress and implicate Nup107 as a critical regulator of the DNA damage-induced intra-S phase checkpoint response. |
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Keywords: | Apoptosome Apaf-1 cell cycle cisplatin DNA damage nucleoporin nuclear pore complex Nup107 |
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