Katsumi Kitagawa, Ph.D.
Associate Professor, Molecular Medicine
The molecular mechanisms that ensure accurate chromosome segregation in mitosis and meiosis are of fundamental importance to the conservation of euploidy in eukaryotes. Errors in this process (e.g., chromosome nondisjunction and chromosome loss) result in aneuploidy—the phenotypic consequences of which are usually profound, including cancer, birth defects, and developmental disorders such as Down syndrome. In humans, errors in chromosome segregation may trigger the onset of neoplasia by uncovering the expression of recessive oncogenic phenotypes, or by contributing to the development of specific aneuploidies. The centromere, a single locus per chromosome, is essential to ensure high fidelity of chromosome transmission. The kinetochore (the protein complex at the centromere) mediates attachment of chromosomes to spindle microtubules and directs chromosome movement during mitosis. Cells have a surveillance system, the spindle checkpoint, which can delay mitotic progression by transiently inhibiting the anaphase-promoting complex in response to defective kinetochore-microtubule attachment. Defects in kinetochore function and the spindle checkpoint result in aneuploidy. Considerable evidence indicates a role of a dysfunctional spindle checkpoint in tumorigenesis.
In most eukaryotes, the centromere is associated with large arrays of repetitive DNA, but has no defined DNA sequence. Consequently, heritability of the centromere is thought to involve epigenetic modifications. CENP-A, the centromeric histone H3 variant, is thought to be a strong candidate for the epigenetic mark. After DNA replication, centromeric nucleosomes, including existing CENP-A, are distributed to the replicated chromatids, and newly synthesized CENP-A deposition occurs at the centromere in G1 in humans. This regulation is crucial for proper centromere inheritance and function. One of our goals is to determine the function of post-translational modifications (PTMs) of CENP-A in the regulation of CENP-A deposition at the centromere and the assembly of kinetochore complexes.
Neocentromeres originate from non-centromeric regions of chromosomes, (i.e., not alpha-satellite DNA). The formation of complex rearranged chromosomes, each containing a neocentromere, has been observed in cancer cells, particularly hematological malignancies. Addition of a neocentromere to a chromosome with an endogenous centromere creates a dicentric state, which results in extensive genomic instability displaying hallmarks of cellular transformation. In colon cancer, CENP-A is overexpressed, and this overexpression is associated with mistargeting of CENP-A to non-centromeric chromatin. These findings suggest that overexpression of CENP-A might cause aneuploidy by creating neocentromeres. In addition, genomic amplification of the CENP-A locus occurred in neuroendocrine prostate cancer (15% of cases) and breast cancer (10% of cases).
Thus, elucidating the mechanism of neocentromere formation will contribute to understanding the mechanism of “cancer evolution” that results in resistance to cancer therapy.