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Remarkably, each specialized cell maintains a memory of its' individual identity by remembering which genes should be on or off, even when making copies of itself. This type of memory is not written directly into the DNA, yet it is transferable to other generations. These non-genetic or "epigenetic" instructions often appear to be contained in proteins, and control not only genes but also how chromosomes are organized.
Lars Jansen and his team, at the Instituto Gulbenkian de Ciência (IGC), Portugal, have worked out how one of these epigenetic organizing centres is faithfully passed on from mother to daughter cells. Their findings not only explain an otherwise mystifying biological process, but provide insight into cell division that can cause cancer when it goes wrong.
The findings feature in the latest issue of the journal Developmental Cell.
The team focused on a unique protein structure on each chromosome, the centromere. The centromere attaches the chromosome to the cell's skeleton (cytoskeleton) during cell division, ensuring that each daughter cell receives exactly one set of freshly made chromosomes. Inaccuracy in cell division results in cells with the wrong number of genes, a hallmark of tumor cells.
Mariana Silva, a PhD student in the lab, and first author of the study, explains "When cells divide they make exactly two copies of all genes, to be passed on to exactly two cells. A similar feat [also] has to be pulled off for non-genetic information. But how does the cell copy a protein structure? And, how does it ensure just the right number of copies are made? This question is still mystifying scientists. We focussed our efforts on the centromere because the key protein responsible for its epigenetic behavior is known."
This protein CENP-A, keeps a "molecular memory" of the centromere, ensuring its inheritance. Previous studies had shown that, while cells duplicate DNA before mitosis, the CENP-A protein duplication of the centromere takes place only after mitosis (during a 'gap' phase called G1). What triggers duplication and how accuracy is ensured remained unknown.
Lars and his team now find that the very same machinery that is controlling DNA duplication is also controlling CENP-A duplication. This machinery includes cyclin-dependent kinases (Cdks) which act as a molecular clock to drive each step of the cell cycle forward, one step at a time. When Cdks are highly active (before mitosis) DNA duplicates and CENP-A duplication is inhibited. Conversely, after mitosis CENP-A is duplicated, but DNA duplication is inhibited. In other words, if DNA duplicates at midnight, Cdks insure the centromere is copied only at noon.
The IGC researchers came to this elegant model by painstainkingly inhibiting Cdk activity in human and chicken cells at set times. When doing so, they could fool the cells into making new centromeres even while the cells were in the middle of duplicating their DNA. "It´s like [seeing] a cell with jetlag", says Lars Jansen.
Lars puts their findings into context: "What we've uncovered is a very simple, neat mechanism whereby the cell couples DNA duplication, cell division and centromere assembly. By using the same machinery (Cdks) for all these steps but in opposite ways, the cell makes sure that the right number of copies of both genes and centromeres are made by allowing each the appropriate time.
Keeping these critical processes separate in time might be important to avoid errors in either one. Understanding these general principles of epigenetic inheritance are fundamental to our understanding of how genes are regulated, how genomes are organised, and the wide spectrum of diseases that result from errors in these mechanisms."
This research was made possible by funding from the Calouste Gulbenkian Foundation (Portugal), Fundação para a Ciência e a Tecnologia (Portugal), the European Commission FP7 program, and the European Molecular Biology Organization (EMBO).
Original article: http://news.wsu.edu/pages/publications.asp?Action=Detail&PublicationID=29223&TypeID=1