PROJECT SUMMARY
Centromeres are chromosomal loci that bind to meiotic or mitotic spindles to facilitate chromosome segregation
and faithful inheritance of genetic information. Errors arising during chromosome segregation can be detrimental
to the cell and cause aneuploidies. The location of the centromere is well maintained; however, how centromeric
DNA encodes the centromere position is not well understood. Centromeric DNA is defined by the presence of
unique centromeric nucleosomes that act as a molecular loading dock for other protein complexes involved in
chromosome segregation. Centromeric nucleosomes contain a histone H3 variant, centromere protein A (CENP-
A). All human centromeres contain repetitive DNA elements known as alpha satellites; however, alpha satellite
sequences vary within a chromosome and between chromosomes. Despite the lack of conserved sequences,
the identity of the centromere is highly maintained. In rare cases, centromeres can form outside of their native
locus, causing the formation of a stable centromere elsewhere in the genome. The formation of ectopic
centromeres, also called neocentromeres, is often associated with chromosomal rearrangements that are found
in developmental disorders and cancers. Patient-derived neocentromeres exhibit a non-random distribution in
the genome, indicating a targeting mechanism to these sites; however, conserved features of the DNA or
chromatin at these sites and at the endogenous centromere have not been discovered yet. This raises interesting
questions about how centromeric DNA is encoded. I hypothesize that the CENP-A nucleosomes that define the
location of the centromere are targeted to unique DNA structures. To address the existing gap in knowledge,
this proposal will use a genomic-based approach to investigate DNA structures and centromere specification.
Understanding the requirements for centromere formation that is necessary for chromosome separation can be
applied to the development of gene therapies and will provide valuable insights into genomic instability that
contributes to disease. This work will allow us to address longstanding questions in the field about how the
localization of centromeres is determined in humans, and through this we will better understand how unique DNA
structures contribute to cellular function and disease.