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

被引:14
作者
Helbling-Leclerc, Anne [1 ,2 ,3 ]
Dessarps-Freichey, Francoise [1 ,2 ,3 ]
Evrard, Caroline [1 ,2 ,3 ]
Rosselli, Filippo [1 ,2 ,3 ]
机构
[1] Gustave Roussy, CNRS, UMR8200, Villejuif, France
[2] Univ Paris Sud, Univ Paris Saclay, Orsay, France
[3] Equipe Labellisee Ligue Canc, Villejuif, France
关键词
CELLULAR SENESCENCE; DNA-DAMAGE; OXIDATIVE STRESS; PATHWAY; CANCER; TUMORIGENESIS; ACTIVATION; DISEASE; BARRIER; BIOLOGY;
D O I
10.1038/s41598-019-53502-w
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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:RAS(G12V) 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.
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页数:11
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