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An international team of researchers led by Matteo Barberis (SILS, UvA), Oscar Aparicio, and Lin Chen (USC, Los Angeles, USA) has demonstrated a mechanism by which chromatin is organised spatially within the nucleus of cells. Their findings have been published in PNAS.

Predicted structure bound to DNA. Image: UvA

The spatial organisation of chromatin within the nucleus regulates pivotal cellular functions such as duplication of a cell’s genetic material (a process called DNA replication), DNA repair upon damage, and timely activation of genes. Specific DNA binding sites, called replication origins, are recognised by enzymes initiating DNA replication and timely cluster prior to initiate this process. The aim of the study was to unravel how these sites are assembled together. The research was conducted using the model organism budding yeast, where the control of DNA replication occurs similarly to human cells.

The researchers have discovered that a specific sequence within a family of proteins, which is evolutionary conserved across species, is responsible for the clustering of replication origins and for the regulation of DNA replication timing. The researchers have demonstrated that these proteins share a structural motif that allows them to bind together (dimerisation) to bring DNA binding sites into close proximity. Mutation that disrupts dimerisation prevents origin clustering and activation, suggesting causality between origin clustering and initiation of DNA replication.

Precise timing

Chromatin changes that occur prior DNA duplication are required for activation of genes at the right timing. Deregulation of this precise timing may result in cells dividing with an unequal number of chromosomes, or with chromosomes not duplicated, as it occurs in a number of diseases. The spatial organization of DNA filaments ensures efficiency of the DNA replication process by increasing the local concentration of specific molecule at DNA binding sites. The findings reveal a conserved mechanism to establish chromatin architecture in eukaryotic organisms, including humans.

Publication details

A. Zachary Ostrow, Reza Kalhor, Yan Gan, Sandra K. Villwock, Christian Linke, Matteo Barberis, Lin Chen and Oscar M. Aparicio: ‘Conserved forkhead dimerization motif controls DNA replication timing and spatial organization of chromosomes in S. cerevisiae’ in PNAS, 6 March 2017