Abstract: The nuclear periphery helps to organize the genome, and assembly of the nuclear lamina is disrupted in a rare premature aging syndrome called Hutchinson-Gilford progeria. Buchwalter set out to determine whether the lamina protein mutated in HGPS, lamin A, accumulates during progeria. Using metabolic labeling to track protein stability, she learned that lamin A and many other proteins are actually turned over more rapidly in patients with progeria.
Following up, she showed that progeroid cells are synthesizing more net proteins than normal cells, requiring greater turnover to achieve homeostasis. This upregulation of protein synthesis may explain, to some extent, the documented loss of heterochromatin in progeroid cells. Indeed, demethylation of repetitive rDNA loci in progeroid cells is dramatically reduced, causeing ribosomal RNAs to be produced at a higher rate. Similarly, more ribosomal proteins are produced, and the rRNAs and RPs get together to create more ribosomes, which in turn lead to higher overall rates of translation.
In progeria, then, we have a widespread disruption of heterochromatin marks, which derepresses rDNA loci and increases the rate of protein synthesis. This causes nucleoli, the site of rRNA production, to expand.
We know that decreasing ribosome biogenesis increases the lifespan. New data from Buchwalter’s lab shows that nucleoli also expand in normal aged individuals — and this phenomenon is conserved in worm, fly, and mouse. For example, in worm, nucleolar size is impressively negatively correlated with lifespan: large nucleoli on the first day of adulthood means a shorter life.
Pioneer: Abby Buchwalter (Assistant Professor/UCSF)
Agent: Chris Patil (Hourglass)