Fanconi anemia signaling network regulates the spindle assembly checkpoint
Grzegorz Nalepa, … , Helmut Hanenberg, D. Wade Clapp
Grzegorz Nalepa, … , Helmut Hanenberg, D. Wade Clapp
Published August 15, 2013
Citation Information: J Clin Invest. 2013;123(9):3839-3847. https://doi.org/10.1172/JCI67364.
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Research Article Hematology

Fanconi anemia signaling network regulates the spindle assembly checkpoint

Abstract

Fanconi anemia (FA) is a heterogenous genetic disease with a high risk of cancer. The FA proteins are essential for interphase DNA damage repair; however, it is incompletely understood why FA-deficient cells also develop gross aneuploidy, leading to cancer. Here, we systematically evaluated the role of the FA proteins in chromosome segregation through functional RNAi screens and analysis of primary cells from patients with FA. We found that FA signaling is essential for the spindle assembly checkpoint and is therefore required for high-fidelity chromosome segregation and prevention of aneuploidy. Furthermore, we discovered that FA proteins differentially localize to key structures of the mitotic apparatus in a cell cycle–dependent manner. The essential role of the FA pathway in mitosis offers a mechanistic explanation for the aneuploidy and malignant transformation known to occur after disruption of FA signaling. Collectively, our findings provide insight into the genetically unstable cancers resulting from inactivation of the FA/BRCA pathway.

Authors

Grzegorz Nalepa, Rikki Enzor, Zejin Sun, Christophe Marchal, Su-Jung Park, Yanzhu Yang, Laura Tedeschi, Stephanie Kelich, Helmut Hanenberg, D. Wade Clapp

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Figure 6

Multiple cell cycle defects may lead to aneuploidy in FA-deficient cells.

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Multiple cell cycle defects may lead to aneuploidy in FA-deficient cells...
Loss of the FA signaling pathway results in abnormal mitosis due to (A) SAC failure (Figures 1–2); (B) presence of supernumerary centrosomes (Figure 5 and Supplemental Figure 11), leading to merotelic kinetochore-spindle attachment, as proposed by Ganem et al. (29); and (C) premature cytokinesis, as reported by Vinciguerra et al. (30). The failed mitosis produces multinucleated cells with ongoing mutagenesis in the micronuclei (36). Since FA-deficient cells cannot efficiently recognize and repair DNA damage (reviewed in refs. 1, 2, 43), this process leads to accumulation of mutations and either cell death or malignant transformation. Centrosomes are shown in yellow, kinetochores are shown in red, DNA is shown in gray, and micronuclei undergoing mutagenesis are shown in purple.