Histone protein supply and demand: life on a knife's edge

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DNA is a polymer that is found in every eukaryotic cell type. DNA encodes all the information necessary to ensure that the cell remains alive and functions properly. In cells, DNA is tightly associated with specialized packaging proteins, known as histones, that organize DNA into a more compact form called the nucleosome. In order to divide into two daughter cells, a cell must not only faithfully duplicate all its DNA, but it also has to make sure that the DNA is free of damage. This is a crucial requirement to ensure that the two daughter cells inherit the correct DNA sequences needed for their viability and proper function. During DNA duplication, many events can go wrong and lead to the accumulation of DNA damage. One of these events is the presence of an excess of histone proteins, which is known to interfere with DNA repair. Accordingly, cells have evolved sophisticated molecular mechanisms to ensure that the amounts of available histone proteins do not exceed the amount of DNA that is being synthesized and needs to be packaged into nucleosomes. The precise nature of these mechanisms, and the way by which they operate to balance histone production and DNA production, is not known. The goal of this research program is to take advantage of the powerful tools available in the baker's yeast, an organism commonly used in biology, to decipher how this works. This will be done by testing our working hypothesis in which a protein called Hpc2, which is known to bind histones and promote the formation nucleosomes , acts as a "sensor" to balance histone production and DNA production. Using yeast will also enable us to perform a powerful experiment, known as a genetic screen, to identify other genes that function in this process. Because DNA and histones form nucleosomes in all eukaryotic organisms, deciphering this regulatory mechanism in yeast will help us shed light into a mechanism that contributes to maintain DNA sequence integrity in a vast number of species that range from the humble baker's yeast all the way to humans.