Challenging nuclear fiction: new roles for old nuclear proteins
Session type: Plenary lectures
The cell nucleus plays crucial roles in cell proliferation and cancer, yet research has often been impeded by flawed concepts. Examples will be drawn from cell differentiation, cell proliferation and intracellular transport of proteins and RNA. In each of these areas flawed concepts and models have been challenged by new insights into the roles of known nuclear proteins.
Duplicating the human genome is a logistical challenge. 105 replication initiation events must be coordinated so that all DNA is duplicated exactly once and only once. The cell keeps track of which regions it has already duplicated by a ratchet-like system of 'replication licensing' that deploys multiple molecular mechanisms to couple DNA replication to the cell cycle.
Proteins that make up the licence are remarkably powerful markers for improving cancer screening and diagnosis. They include proteins called minichromosome maintenance (MCM) proteins and a small protein called geminin. Together with cyclins they ensure that one round of chromosome duplication is complete before the next can start.
Remarkably geminin also has a novel role in specifying stem cell identity by regulating the expression of the pluripotency factors that programme stem cells. Removal of geminin from mouse embryonic stem cells has two dramatic and independent effects. Predictably they become enormous by synthesising DNA repeatedly without dividing, but they also lose their stem cell identity by differentiating.
An inadequate model also restrained research into how proteins are imported into the nucleus. Overturning it allowed rapid identification of import signals and their receptors (importins). Similarly, models of mRNA export from the nucleus may be too simple. We and others have found examples of nuclear proteins that act as selective mRNA export factors. One of these selectively exports mRNAs that influence gene expression and another enhances export of mRNAs for proteins that repair double stranded breaks in DNA.