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Fanconi anemia proteins counteract the implementation of the oncogene-induced senescence program.

ABSTRACT: Fanconi Anemia (FA), due to the loss-of-function of the proteins that constitute the FANC pathway involved in DNA replication and genetic stability maintainance, is a rare genetic disease featuring bone marrow failure, developmental abnormalities and cancer predisposition. Similar clinical stigmas have also been associated with alterations in the senescence program, which is activated in physiological or stress situations, including the unscheduled, chronic, activation of an oncogene (oncogene induced senescence, OIS). Here, we wanted to determine the crosstalk, if any, between the FANC pathway and the OIS process. OIS was analyzed in two known cellular models, IMR90-hTERT/ER:RASG12V and WI38-hTERT/ER:GFP:RAF1, harboring 4-hydroxytamoxifen-inducible oncogenes. We observed that oncogene activation induces a transitory increase of both FANCA and FANCD2 as well as FANCD2 monoubiquitination, readout of FANC pathway activation, followed by their degradation. FANCD2 depletion, which leads to a pre-senescent phenotype, anticipates OIS progression. Coherently, FANCD2 overexpression or inhibition of its proteosomal-dependent degradation slightly delays OIS progression. The pro-senescence protease cathepsin L, which activation is anticipated during OIS in FANCD2-depleted cells, also participates to FANCD2 degradation. Our results demonstrate that oncogene activation is first associated with FANCD2 induction and activation, which may support initial cell proliferation, followed by its degradation/downregulation when OIS proceeds.

SUBMITTER: Helbling-Leclerc A

PROVIDER: S-EPMC6863893 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Fanconi anemia proteins counteract the implementation of the oncogene-induced senescence program.

Helbling-Leclerc Anne A Dessarps-Freichey Françoise F Evrard Caroline C Rosselli Filippo F

Scientific reports 20191119 1

Fanconi Anemia (FA), due to the loss-of-function of the proteins that constitute the FANC pathway involved in DNA replication and genetic stability maintainance, is a rare genetic disease featuring bone marrow failure, developmental abnormalities and cancer predisposition. Similar clinical stigmas have also been associated with alterations in the senescence program, which is activated in physiological or stress situations, including the unscheduled, chronic, activation of an oncogene (oncogene i ...[more]

PMID: 31745226

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Project description:This experiment was designed to study oncogene-induced senescence (OIS). To this end we generated a series of cell lines derived from normal human diploid fibroblasts IMR90 forced to express the catalytic subunit of telomerase (hTERT). This cells were then subjected to further manipulation by orderly introducing defined genetic elements by retroviral transduction. The first cell line generated was ITV, which was obtained from the original cell line (IMR90 with hTERT) after introducing an empty vector. Subsequently, we introduced Mek:ER, which is a switchable version of the Mek kinase, a relevant downstream effector of Ras signaling during Ras-induced senescence, to generate ITM cells. We further modified this cell line by introducing SV40 small-t antigen (ST), papillomavirus oncoproteins E6 and E7 (E6/E7) or the combination of both (E6/E7 and ST). In this manner, we obtained ITMST, ITME6E7 and ITME6E7ST respectively. This cellular system allow us to have a representation of the different steps into neoplastic transformation. ITM and ITMST cells respond to Mek activation by inducing OIS. ITME6E7 and ITME6E7ST cells do not enter OIS after Mek activation. Mek activation is achieved by treating all cell cultures with 4-hydroxytamoxifen (4OHT) at 100 nM, in the absence of serum, and for 3 days. The gene expression profile of ITV cells served as a reference for all the expression values obtained with the rest of the cell lines. Thus, we ended up with the expression profiles of two cell lines representing oncogene-induced senescence (ITM and ITMST), and two cell lines representing bypass of oncogene-induced senescence, plus a reference profile provided by ITV, the cell line from which all the other cell lines were derived. Our final goal was to identify markers of the oncogene-induced senescence response by comparing the expression profiles of the cell lines entering OIS after Mek activation (that is, after 4OHT treatment) with the ones bypassing this response. Keywords: other

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Fanconi anemia proteins counteract the implementation of the oncogene-induced senescence program.

Publications

Fanconi anemia proteins counteract the implementation of the oncogene-induced senescence program.

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