Key Mechanism in Genetic Inheritance During Cell Division Identified

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Medical News Today 02 Feb 2005

Key Mechanism in Genetic Inheritance During Cell Division Identified

A key mechanism in the passing of genetic material from a parent cell to

daughter cells appears to have been identified by a team of Berkeley

researchers. Their study may explain how a complex of proteins, called

kinetochores, can recognize and stay attached to microtubules, hollow fibers in

the walls of biological cells that are responsible for the faithful segregation

of chromosomes during cell division.

“In test tube experiments, we've found that the kinetochore proteins form rings

around the microtubules and this ring formation promotes microtubule assembly,

stabilizes against disassembly, and promotes bundling,” says Eva Nogales, a

biophysicist who holds joint appointments with the Lawrence Berkeley National

Laboratory (Berkeley Lab), the University of California at Berkeley, and the

Medical Institute (HHMI). “If ring formation takes place in vivo,

it could be the mechanism by which chromosomes are kept segregated during

mitosis.”

Nogales is one of the co-authors of a paper reporting the results of this

research which appears in the January 21, 2005 issue of the journal Molecular

Cell. Other authors of the Molecular Cell paper were Georjana ,

Drubin and Stefan Westermann, with UC Berkeley's Department of Molecular and

Cell Biology, who were the lead investigators on this work, plus Agustin

Avila-Sakar and Hong-Wei Wang, with Berkeley Lab, and Hanspeter Niederstrasser

and Wong with UC Berkeley.

Says , “Mistakes in chromosome segregation during mitosis contribute to

cancer and birth defects. From various genetic experiments we know that the

activity of a 10-protein complex of kinetochores, called Dam1, is responsible

for the faithful segregation of chromosomes during mitosis. While we don't know

at this time that ring formation occurs in vivo, we do see in our in vitro tests

that Dam1 ring formation strengthens the microtubules.”

Thousands of microtubule fibers are woven together to form a highly flexible

cytoskeleton in biological cells that gives shape to cell walls and other

structures, and controls the transportation of substances in and out of a cell.

During cell division (mitosis), the microtubule fibers disassemble and reform

into spindles across which duplicate sets of chromosomes line up. During this

phase, it is critical that the spindles maintain their structural integrity so

that they can segregate a single copy of each chromosome to each daughter cell.

After which, the microtubules again disassemble and reform back into skeletal

systems for the two new daughter cells. It has been determined, through the

genetic research of and Drubin, among others, that kinetochores must bind

to a microtubule spindle to avoid the gain or loss of chromosomes by each of the

daughter cells. How this works, however, was unknown.

To find answers, the Berkeley researchers used a purified, reconstituted Dam1

complex, obtained from genetically engineered E. coli bacteria, and compared its

effects on microtubules in vitro to the effects caused by certain Dam1 mutants.

Their analysis shed new light on the structural nature of the

kinetochore-microtubule interface, and may provide a biochemical explanation for

the role of kinetochores in maintaining chromosome segregation during mitosis.

“Our studies indicate that the Dam1 rings are formed by longitudinal

self-assembly of multiple copies of the Dam1 complex upon the microtubule

surface,” the authors state in their Molecular Cell paper. “Although the

presence of microtubules strongly facilitates the oligomerization process, ring

assembly seems to be an intrinsic property of the Dam1 complex, as we have been

able to induce self-assembly into rings in the absence of microtubules.”

The formation of rings around the microtubules by the purified Dam1 complex that

the Berkeley collaborators observed has not been reported for any other

microtubule binding protein complex. While the authors say that ring formation

is a complicated way to construct a microtubule binding structure, a microtubule

binding ring might be uniquely suited to fulfill the functions of the Dam1

complex. In comparison with the purified Dam1, the Dam1 mutants produced

partially formed rings that reduced microtubule binding.

“Because the stability of a microtubule is thought to be largely governed by the

lateral interactions between adjacent protofilaments,” the authors note, “rings

that bind orthogonally to the microtubule axis are not only expected to

strengthen interprotofilament interactions, but to also prevent protofilament

peeling, which in turn would encourage further growth.

Furthermore, the Berkeley researchers showed that binding between the ring and

the microtubule is mediated by flexible domains, and is largely electrostatic in

nature. This could allow for lateral sliding or diffusion of Dam1 rings along

microtubules. Analysis of the Dam1 rings after disassembly of microtubules,

revealed an accumulation of rings at the ends of the microtubule, suggesting

that the rings do not disassemble but slide back as the microtubule

protofilaments peel away from the ends.

Says Nogales, “That the rings remain attached to the microtubule end as it

depolymerizes, is a most ingenious mechanism to move chromosome to the two

daughter cells during anaphase, without even requiring energy. This is great

finding!”

Berkeley Lab is a U.S. Department of Energy national laboratory located in

Berkeley, California. It conducts unclassified scientific research and is

managed by the University of California.

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