Indiana University-Purdue University Indianapolis (IUPUI) / The Fanconi anemia (FA) pathway consists of 21 genes that maintain genomic stability
and prevent cancer. Biallelic mutations within this network cause Fanconi anemia, an
inherited bone marrow failure and cancer predisposition syndrome. Heterozygous inborn
mutations in FA genes increase risk of breast/ovarian cancers, and somatic mutations
occur in malignancies in non-Fanconi patients. Understanding the tumor suppressive
functions of FA signaling is important for the study of Fanconi anemia, inherited cancers,
and sporadic cancers.
The FA network functions as a genome guardian throughout the cell cycle. In addition to
the well-established roles of FA proteins in interphase DNA replication/repair, the FA
pathway controls mitosis by regulating the spindle assembly checkpoint (SAC) to ensure
proper chromosome segregation. The SAC consists of several tumor suppressors,
including Mad2, and SAC impairment predisposes to aneuploidy and cancer. However,
the in vivo contribution of SAC dysfunction to malignant transformation of FA-deficient
cells remains unknown. Furthermore, the mechanisms by which FA proteins regulate the
SAC are unclear.
To test whether SAC dysfunction drives genomic instability and tumorigenesis in FA, we
generated a novel FA-SAC model by intercrossing Fancc-/- and Mad2+/- mice. The intercrossed mice displayed heightened aneuploidy secondary to exacerbated SAC
dysfunction. Importantly, these mice were prone to developing hematologic
malignancies, particularly leukemia, faithfully recapitulating the clinical phenotype of
Fanconi anemia.
Upon establishing SAC dysfunction as a driver of tumorigenesis in FA, we next explored
the mechanism by which FANCC regulates the SAC. We demonstrated that the mitotic
kinase CDK1 phosphorylates FANCC to regulate subcellular localization and SAC
function of FANCC during mitosis.
Our study highlights the essential role of compromised chromosome segregation in the
development of leukemia due to impaired FA signaling. This work furthers our
knowledge of FANCC signaling at the SAC, and has implications for future use of
mitotic-centered therapies for FA-associated tumors. / 2 years
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/13391 |
| Date | 27 March 2017 |
| Creators | Edwards, Donna Marie |
| Contributors | Clapp, D. Wade, Nalepa, Grzegorz, Harrington, Maureen A., Goebl, Mark G. |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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