Image courtesy of Dr. Susan Parkhurst / Current Biology 2015
Scientists at Fred Hutchinson Cancer Research Center have found a protein that helps shape the nucleus, a special compartment within cells that houses and controls genetic information. When cells are missing that protein, known as Wash, nuclei lose their classic plump shape and become wrinkled and puckered.
Nuclei pucker in the natural aging process and in certain diseases including progeria, a rare and fatal genetic disorder that dramatically speeds up aging. Whether Wash plays a role in progeria or aging is still unclear, but these findings are an intriguing hint that it might, said Dr. Susan Parkhurst, a biologist at Fred Hutch.
The way Wash keeps those microscopic wrinkles at bay is unusual because the protein performs a similar function not just in the nucleus but throughout the rest of cell.
If you imagine a cell looking somewhat like a fried egg, the nucleus is the yolk and the cytoplasm, the rest of the cell, is the white. Though they are only microscopic steps apart, these compartments are very different from each other. It’s rare for proteins to carry out tasks in both compartments, and it’s never been seen before for a structural protein like Wash, Parkhurst said, except in cases where such proteins play a different role in the nucleus.
Looking at fruit flies’ cells and embryos, the researchers also found that Wash interacts with a protein called Lamin B that is closely related to a protein known to drive progeria. The lamin proteins form a mesh that lines the inside of the nucleus, helping to keep its shape. Children with progeria are born with a tiny mutation in a gene coding for a related protein, Lamin A.
That mutation was discovered in 2003 by a team of genetic researchers, spurred by a scientist and mother of a child with progeria who founded the Progeria Research Foundation to help chip away at the mysteries of the disease. Although progress has been made in the intervening 12 years, scientists still don’t fully understand how mutated Lamin A triggers the disease or how nuclear puckering is connected with progeria and old age.
Both Wash and Lamin B are needed to maintain the nucleus’ normal form, like that of a tiny round grape. When either Wash or Lamin B is missing, the nucleus shrivels, raisin-like. Parkhurst and her team found that Wash-deficient nuclei shrink to about two-thirds of their natural size.
Shape matters for the cell and its nucleus
“Just like the cell has to have a shape … so does the nucleus, and nobody’s really ever shown how that infrastructure is set up,” Parkhurst said.
Parkhurst and her colleague, Fred Hutch biologist Dr. Barbara Trask, found the human equivalent of Wash eight years ago and turned to the fruit fly to uncover the protein’s role in building that framework. They found that in the cytoplasm, Wash helps build the scaffolding that shapes cells and traffics important cargo from place to place.
But so far, nobody has found proteins that shape the scaffolding of both the nucleus and cytoplasm, so the researchers were surprised to find that Wash is also present in abundance in the nucleus.
“This is different from what most cytoplasmic proteins are thought to do,” Parkhurst said.
Though it’s mostly water, the cytoplasm is highly structured. Protein highways crisscross the fluid, keeping the cell from collapsing on itself, shuttling molecules from point A to point B and helping cells divide in two.
Scientists understand many of the players within the cytoplasm’s scaffolding system, but even though the nucleus needs to carry out similar tasks, how it does so is fairly mysterious, Parkhurst said.
“We know how things move inside cells; we don’t know how they move in the nucleus. But things need to move,” she said.
Their work implies that Wash could be responsible for some of these functions. As such, the researchers may be able to infer a lot about the nucleus’ structure and transport from Wash’s activity in the cytoplasm, where that activity is better understood.
The mystery of DNA transport
Parkhurst and her colleagues found that not only do nuclei crumple when Wash is missing, but the genetic information inside also falls into disarray. Normally, DNA is organized not only linearly on chromosomes, but in 3-D compartments inside the nucleus. That spatial organization helps regulate gene activity. For example, some spots in the nucleus are dead zones, in which all genes are turned off. When cells need to activate those genes, they have to physically transport the gene from the dead zone to an active zone. How DNA moves from zone to zone is not understood.
To explore Wash’s role in nuclear organization, Parkhurst turned to molecular biologist and Fred Hutch’s Executive Vice President and Deputy Director Dr. Mark Groudine, an expert in the geography of the nucleus. The team found that when Wash is missing, those compartments partially dissipate too. Chromosomes appear more twisted under the microscope in mutant cells and are more fragile, breaking easily under physical stress.
Since the nuclei of Wash-deficient cells look a lot like aging nuclei, it’s conceivable that this protein plays a role in natural aging, Parkhurst said, but it’s too soon to say for certain. The protein seems to be so critical for many parts of cell biology that Parkhurst first wants to focus on its basic role. Even though it may prove important in progeria and related diseases, we must first understand how the protein functions at a fundamental level in all of our cells, she said.
“If we don’t really understand the mechanism it’s using in cell biology, it won’t help us with the diseases,” Parkhurst said. “All it will be is correlative instead of informative.”
Dr. Rachel Tompa is a staff writer at Fred Hutchinson Cancer Research Center. She joined Fred Hutch in 2009 as an editor working with infectious disease researchers and has since written about topics ranging from nanotechnology to global health. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Reach her at firstname.lastname@example.org.
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