Project Details
Description
The composition, organization, and function of centromeric DNA remain one of the last frontiers of
genomics. This proposal “Centromeres and Ovarian Cancer” will investigate the role centromere DNA
sequences play in the correct function of centromeres and chromosome segregation in ovarian cancer,
and its contribution to ovarian cancer progression. The centromere is the functional unit responsible for the
faithful segregation of chromosomes. Failure to properly partition chromosomes to daughter cells results in
genome instability and aneuploidy (gain or loss of chromosomes), a hallmark of cancers. Functional centromere
structures are made of centromere epigenetic marks that bind to the underlying DNA sequence. During cell
division, the microtubules interact with these centromeric structures and pull chromosomes apart. Although
centromere identity and function rely on epigenetic mechanisms, recent studies suggest that centromere
sequences have functional roles as well. However, human centromere sequences have not been assembled
into linear contigs due to their high content of repetitive DNA, and thus, the precise composition, organization,
and function of centromeric DNA remain to be elucidated. We will investigate the role centromere DNA
sequences play in centromere function and chromosome segregation in ovarian cancer. To overcome the virtual
absence of centromere sequence in the Human Genome Project, the P.I. has devised rapid, quantitative PCR-
based methods and innovative Next Generation Sequencing tools to study specifically the centromeric DNA
elements of each human chromosome at the molecular level. Using these pioneering technologies, we
discovered that the genomes of ovarian cancer cells exhibit severe loss of centromere sequences in specific
chromosomes, in particular chromosome 17, when compared to healthy matched-tissue. We hypothesize that
these specific centromere mutations play a key role in centromere formation and function, and lead to
chromosome 17 missegregation and genome instability seen in ovarian cancer. The proposed research will use
mutant ovarian and fallopian tube cell lines with centromere deletions generated using CRISPR Cas9. We will
investigate whether centromere loss alters the ability of centromeric epigenetic marks to form
centromere/kinetochore structures. We will address whether loss of centromeric material in these mutant cells
affects genome stability, chromosome segregation and transformation. This information will begin to provide a
better understanding of the role’s centromere sequences play in cell division and cancer genetics. These studies
will enhance our knowledge of centromeres and chromosomal biology and could potentially result in novel
methodologies to study genetic defects in cancers.
Status | Active |
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Effective start/end date | 9/23/22 → 8/31/24 |
Funding
- National Cancer Institute: $408,829.00
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