Fanconi anemia signaling network regulates the spindle assembly checkpoint.
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.
Division of Pediatric Hematology-Oncology, Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. gnalepa@iu.edu
Grzegorz
G
Nalepa
Rikki
R
Enzor
Zejin
Z
Sun
Christophe
C
Marchal
Su-Jung
SJ
Park
Yanzhu
Y
Yang
Laura
L
Tedeschi
Stephanie
S
Kelich
Helmut
H
Hanenberg
D Wade
DW
Clapp
D000941:Antigens / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D018385:Centrosome / Q000378:metabolism; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000502:physiology; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints; D008938:Mitosis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D008941:Spindle Apparatus / Q000378:metabolism
D000941:Antigens; D051856:Fanconi Anemia Complementation Group Proteins; D034741:RNA, Small Interfering; C086178:pericentrin