Research Seminar: Katsumi Kitagawa, Pharm.D., PhD (Greehey CCRI)

Kitagawa Lab Research

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 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 the 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 the defective kinetochore-microtubule attachment. Defects in the 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 vast arrays of repetitive DNA but has no defined DNA sequence. Consequently, the heritability of the centromere is thought to involve epigenetic modifications. CENP-A, the centromeric histone H3 variant, is believed 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. However, the molecular mechanism that determines the precise CENP-A deposition epigenetically remains obscure. One of our aims 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. The contribution of our work will be significant because understanding the role of PTMs of CENP-A in regulating centromere formation should advance the understanding of the development of diseases associated with chromosome instability (CIN), such as tumors.

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. The 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, the CENP-A is overexpressed, and this overexpression is associated with the mistargeting of CENP-A to non-centromeric chromatin. These findings suggest that overexpression of CENP-A might cause aneuploidy by creating neocentromeres. Genomic amplification of the CENP-A locus occurred in neuroendocrine prostate cancer (15% of cases) and breast cancer (10% of cases). We have found that CENP-A is highly expressed in several pediatric tumors.

Thus, elucidating the mechanism of neocentromere formation will contribute to understanding the mechanism of “cancer evolution” that results in resistance to cancer therapy.

We will investigate the role of aneuploidy in the development of pediatric cancers.

Learn more about Dr. Kitagawa's research