PgmNr D1483: Determining how chromatin structure impacts DNA replication and cell cycle progression.

Authors:
Robin L. Armstrong; Robert J. Duronio


Institutes
University of North Carolina at Chapel Hill, Chapel Hill, NC.


Keyword: histone variants and modifications

Abstract:

Temporal control of DNA replication is essential for maintenance of cellular proliferation and homeostasis, where loss of control can result in genomic instability, developmental abnormalities, and cancer. Origins of replication act in cis to establish temporal control of DNA replication through cell cycle-controlled recruitment of trans-acting factors. Metazoan studies have yet to find a consensus sequence associated with origins where, instead, origin definition is suggested to be strongly influenced by chromatin architecture, comprised of both nucleosome density and histone tail post-translational modifications (PTMs). PTMs modulate nucleosome density along a DNA molecule, establishing chromatin states that are either “open” or “closed” to protein complexes required for DNA replication.

Chromatin PTMs that contribute to heterochromatin formation and those associated with early origin firing and replication timing are being investigated to address central questions including whether specific histone PTMs are required for origin definition and replication timing, whether PTMs that define heterochromatin are required to create conditions permissive for heterochromatin replication during late S-phase, and whether specific PTMs function in cell cycle regulation. Using a Drosophila melanogaster histone replacement platform, we show that specific histone PTMs function in cell cycle control, regulation of DNA replication, and concentration of trans-acting factors.