Defective cell proliferation is an attribute of overexpressed Notch1 receptor and impaired autophagy in Fanconi Anemia

Fanconi Anemia (FA) is an inherited bone marrow failure syndrome caused by mutation in FA pathway proteins, involved in Interstrand Cross Link (ICL) repair. FA cells exhibit in vitro proliferation arrest due to accumulated DNA damage, hence understanding the rescue mechanism that renders proliferati...

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Published in:Genomics (San Diego, Calif.) Calif.), 2020-11, Vol.112 (6), p.4628-4639
Main Authors: Zipporah E, Binita, Patra, Bamadeb, Govarthanan, Kavitha, Yadav, Rajesh, Mohan, Sheila, Shyamsunder, Pavithra, Verma, Rama Shanker
Format: Article
Language:English
Subjects:
Autophagy
Cell proliferation
Fanconi Anemia
Gene expression
Notch signalling
Rapamycin
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Summary:Fanconi Anemia (FA) is an inherited bone marrow failure syndrome caused by mutation in FA pathway proteins, involved in Interstrand Cross Link (ICL) repair. FA cells exhibit in vitro proliferation arrest due to accumulated DNA damage, hence understanding the rescue mechanism that renders proliferation advantage is required. Gene expression profiling performed in FA patients Peripheral Blood Mononuclear Cells (PBMCs) revealed a wide array of dysregulated biological processes. Functional enrichment and gene clustering analysis showed crippled autophagy process and escalated Notch signalling pathway in FA clinical samples and cell lines. Notch pathway mediators overexpression were reverted in FANCA mutant cells when treated with Rapamycin, an autophagy inducer. Additionally, Rapamycin stabilized cell viability after treatment with the DNA damaging agent, MitomycinC (MMC) and enhanced cell proliferation genes expression in FANCA mutant cells. Inherently FANCA mutant cells express impaired autophagy; thus activation of autophagy channelizes Notch signalling cascade and sustains cell viability. •Fanconi Anemia displays underexpressed autophagy markers.•Enhanced Notch signalling is an outcome of defective autophagy process.•Rapamycin-induced autophagy attenuates Notch upregulation and enhances the expression of proliferation markers in FA.
ISSN:0888-7543
1089-8646
DOI:10.1016/j.ygeno.2020.08.009