Jan. 13, 2008 At the Institut Curie, the CNRS team of Geneviève Almouzni(1) has just discovered how the protein Asf1 ensures the correct (re)organization of duplicated DNA. During DNA replication, all the information in the mother cell must be transmitted to the daughter cells. The DNA must be faithfully copied, of course, but also properly organized within the cell. DNA is wrapped around proteins called histones, to form chromatin.
This complex structure contains so-called epigenetic information, which governs gene expression and gives each cell its specific identity. The histone chaperone, Asf1, coordinates the removal of histones from the chromatin to allow the replication machinery to move along the DNA, with the supply of new histones to reform the chromatin once the replication machinery has passed. This discovery sheds new light on the transmission of epigenetic information in cells, and was published in the 21 December 2007 issue of Science.
DNA inherited from both parents is copied during each cell division and transmitted to all cells. Each of our cells therefore contains the same genetic information. So, what is the difference between a neuron and a white blood cell? The difference lies in the fact that although every cell in our body has the same number of genes, only some of these genes are active in any given cell. Depending on cell type, certain genes are “locked” to prevent their expression.
Information on the locking and unlocking of genes is essential for cell function, and is not carried in the genes themselves but by epigenetic factors. These can be chemical modifications(2) or the organization of the DNA within the cell. The DNA double helix (diameter 2 nanometers) is wrapped around histones, proteins that facilitate its compaction, to form nucleosomes, which are strung along the DNA like beads on a string. This bead necklace then folds on itself to form a fiber—chromatin.
When a cell divides to give rise to two daughter cells, the DNA-replicating machinery unfolds the chromatin as it moves along the DNA strands. Once the so-called replication fork (the structure that forms during DNA replication) has passed, both the DNA and the epigenetic factors must be repositioned. The “Chromatin Dynamics” team of Geneviève Almouzni (UMR 218 CNRS/Institut Curie) has now shown that the histone chaperone, the protein ASF-1, regulates the progression of the replication fork, and handles the supply and demand of histones during this process essential to cell life.
Asf1 oversees the removal of old histones upstream of the replication fork, and their recycling, together with the supply of newly synthesized histones to the DNA daughter strands. In so doing, Asf1 collaborates with MCM2-7, a protein complex that opens the DNA strands to allow the replication fork to advance. Asf1 therefore plays a key role in replication during cell division by coordinating the recycling of old histones and the incorporation of newly synthesized histones.
This discovery clarifies the relation between duplication of the genetic material and transmission of information carried by the histones during cell division. Any alterations occurring in the DNA or chromatin may compromise the development of an organism or play a part in cell aging, or even in the occurrence of cancer. This discovery sheds new light on the role of epigenetics in cancer development.
(1) Geneviève Almouzni is a CNRS director of research and heads the CNRS/Institut Curie Laboratory of Nuclear Dynamics and Genome Plasticity.
(2) Such as the binding of chemical groups (methyl, phosphate, acetyl) to DNA and to its associated proteins, the histones.
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