Chromosome inheritance ensures transmission of genetic information. Abnormal chromosome segregation severely affects the health and viability of all cells and organisms. Errors in chromosome inheritance lead to chromosome abnormalities (aneuploidy) that cause many birth defects, such as Down Syndrome and miscarriages, and are the hallmarks of almost all types of cancers. The centromere, a complex of DNA and proteins, is central to the chromosome inheritance process and contributes to formation of the kinetochore, heterochromatin and sister chromatid cohesion. Defects in centromere functions lead to aneuploidy or tumor formation in yeast, flies and mice. CENP-A, a conserved H3-1ike histone that replaces H3 in centromeric nucleosomes, is the structural and functional foundation of the kinetochore and adjacent centromeric region. We have shown that kinetochore chromatin is uniquely arranged as interspersed domains of CENP-A and H3 nucleosomes that promote a specialized cylindrical structure on metaphase chromosomes. This special structure is formed on divergent DNA sequences, and it is not known how centromeric chromatin is established and maintained, nor the structural and functional aspects if it is altered. The goal of this proposal is to apply an integrative, dual-system approach, using novel reagents and techniques that I have developed in my former lab, to test key organizational and functional aspects of centromeric chromatin in Drosophila and humans. We propose to investigate the roles of genomic structure and chromatin organization and dynamics in assembly and regulation of CENP-A chromatin, centromeric domains, and metaphase kinetochore structure.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cell Development and Function Integrated Review Group (CDF)
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Carter, Anthony D
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Duke University
Schools of Medicine
United States
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Sullivan, Lori L; Maloney, Kristin A; Towers, Aaron J et al. (2016) Human centromere repositioning within euchromatin after partial chromosome deletion. Chromosome Res 24:451-466
Maloney, Kristin A; Sullivan, Lori L; Matheny, Justyne E et al. (2012) Functional epialleles at an endogenous human centromere. Proc Natl Acad Sci U S A 109:13704-9
Sullivan, Lori L; Boivin, Christopher D; Mravinac, Brankica et al. (2011) Genomic size of CENP-A domain is proportional to total alpha satellite array size at human centromeres and expands in cancer cells. Chromosome Res 19:457-70
Stimpson, Kaitlin M; Song, Ihn Young; Jauch, Anna et al. (2010) Telomere disruption results in non-random formation of de novo dicentric chromosomes involving acrocentric human chromosomes. PLoS Genet 6:
Kim, Jung-Hyun; Ebersole, Thomas; Kouprina, Natalay et al. (2009) Human gamma-satellite DNA maintains open chromatin structure and protects a transgene from epigenetic silencing. Genome Res 19:533-44
Mravinac, Brankica; Sullivan, Lori L; Reeves, Jason W et al. (2009) Histone modifications within the human X centromere region. PLoS One 4:e6602
Lam, Ai Leen; Boivin, Christopher D; Bonney, Caitlin F et al. (2006) Human centromeric chromatin is a dynamic chromosomal domain that can spread over noncentromeric DNA. Proc Natl Acad Sci U S A 103:4186-91
Lam, Ai Leen; Pazin, Dorothy E; Sullivan, Beth A (2005) Control of gene expression and assembly of chromosomal subdomains by chromatin regulators with antagonistic functions. Chromosoma 114:242-51
Sullivan, Beth A; Karpen, Gary H (2004) Centromeric chromatin exhibits a histone modification pattern that is distinct from both euchromatin and heterochromatin. Nat Struct Mol Biol 11:1076-83