FANCA safeguards interphase and mitosis during hematopoiesis in vivo

The Fanconi anemia (FA/BRCA) signaling network controls multiple genome-housekeeping checkpoints, from interphase DNA repair to mitosis. The in vivo role of abnormal cell division in FA remains unknown. Here, we quantified the origins of genomic instability in FA patients and mice in vivo and ex viv...

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Bibliographic Details
Published in:Experimental hematology 2015-12, Vol.43 (12), p.1031-1046.e12
Main Authors: Abdul-Sater, Zahi, Cerabona, Donna, Potchanant, Elizabeth Sierra, Sun, Zejin, Enzor, Rikki, He, Ying, Robertson, Kent, Goebel, W. Scott, Nalepa, Grzegorz
Format: Article
Language:English
Subjects:
Advanced Basic Science
Animals
Fanconi Anemia - genetics
Fanconi Anemia - metabolism
Fanconi Anemia - pathology
Fanconi Anemia - therapy
Fanconi Anemia Complementation Group A Protein - genetics
Fanconi Anemia Complementation Group A Protein - metabolism
Female
Hematology, Oncology and Palliative Medicine
Hematopoiesis
Humans
Interphase
Male
Mice
Mice, Knockout
Mitosis
Spindle Apparatus - genetics
Spindle Apparatus - metabolism
Spindle Apparatus - pathology
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Summary:The Fanconi anemia (FA/BRCA) signaling network controls multiple genome-housekeeping checkpoints, from interphase DNA repair to mitosis. The in vivo role of abnormal cell division in FA remains unknown. Here, we quantified the origins of genomic instability in FA patients and mice in vivo and ex vivo. We found that both mitotic errors and interphase DNA damage significantly contribute to genomic instability during FA-deficient hematopoiesis and in nonhematopoietic human and murine FA primary cells. Super-resolution microscopy coupled with functional assays revealed that FANCA shuttles to the pericentriolar material to regulate spindle assembly at mitotic entry. Loss of FA signaling rendered cells hypersensitive to spindle chemotherapeutics and allowed escape from the chemotherapy-induced spindle assembly checkpoint. In support of these findings, direct comparison of DNA crosslinking and anti-mitotic chemotherapeutics in primary FANCA− / − cells revealed genomic instability originating through divergent cell cycle checkpoint aberrations. Our data indicate that FA/BRCA signaling functions as an in vivo gatekeeper of genomic integrity throughout interphase and mitosis, which may have implications for future targeted therapies in FA and FA-deficient cancers.
ISSN:0301-472X
1873-2399
DOI:10.1016/j.exphem.2015.08.013