Experiments decipher key piece of the ‘histone code’ in cell division

Aug 16, 2010
Credit: Rockefeller University

Reproduce or perish. That’s the bottom line for genes. Because nothing lives forever, reproduction is how life sustains itself, and it happens most fundamentally in the division and replication of the cell, known as mitosis. Now new research at Rockefeller University has detailed a key role in mitosis for a chemical modification to histone proteins that package lengthy strings of DNA into compact chromosomes.

The experiments, published Thursday in Science, add to an increasingly intricate picture of the precisely timed events that separate new copies of to most fundamental processes involved in the reproduction of life.

“We’ve known that histones become decorated during mitosis for more than 30 years, but we haven’t really understood their function,” says Hironori Funabiki, head of the Laboratory of Chromosome and . “Now we’ve finally decoded exactly how one of these marks works.”

Funabiki says the findings provide hard evidence for the “histone code hypothesis,” advanced by Rockefeller’s C. David Allis and colleagues, which suggests that combinations of histone modifications attract or remove specific proteins, controlling the immediate environment of chromosomes in the cell. The orchestration of the exact timing and localization of the vast array of molecules and processes involved in reproducing the chromosomes is one of the basic wonders of biology and is at the core of both healthy living and diseases such as cancer, that arise when the process goes awry.

Funabiki, postdoctoral associate Alex Kelly, graduate student Cristina Ghenoiu and their colleagues focused on the addition of a phosphate group to histone H3 at the site theronine 3 (H3T3); it was first identified in 1980, but its function has remained a mystery. The researchers built on their previous work singling out the chromosomal passenger complex, a group of proteins in the cell that includes the enzyme Aurora B. This complex must be brought to chromosomes and activated to facilitate the assembly of cellular scaffolding called spindle microtubules, which are required to separate chromosomes in a dividing cell. In a series of new experiments, they showed that another member of the complex, Survivin (it’s highly similar to a class of proteins known to stem the process of programmed cell death, or apoptosis) recognizes the phosphate group at H3T3 and, in turn, activates Aurora B.

The researchers found that the phosphate group must be removed after the chromosomes are segregated so that the chromosomes can be properly repackaged to repeat the process over again, and they showed that the enzyme Haspin plays a role in adding the phosphate group that Survivin recognizes and is necessary for the chain of events to come off smoothly. Since both Survivin and Aurora B have been implicated in many cancers, molecules that disrupt the interaction between histone H3 and Survivin could allow for a new avenue for targeted therapeutics.

The study also shows that how Survivin recognizes H3T3 phosphorylation is very similar to how “inhibitor of apoptosis” proteins (IAPs) bind to their own ligands, whose mimetics have been investigated as anti-cancer drugs. “It brings a lot of fields together. I think it will be exciting to a lot of people working on epigenetics, apoptosis and the cell cycle,” Kelly says. “We cracked one code,” Funabiki says, “but there are yet many to be decoded to understand how chromosomes orchestrate mitosis.”

Science online: August 12, 2010
Survivin Reads Phosphorylated Histone H3 Threonine 3 to Activate the Mitotic Kinase Aurora B
Alexander E. Kelly, Cristina Ghenoiu, John Z. Xue, Christian Zierhut, Hiroshi Kimura and Hironori Funabiki

Explore further: Researchers successfully clone adult human stem cells

More information: DOI: 10.1126/science.1189505

add to favorites email to friend print save as pdf

Related Stories

The Watchdogs of chromosome-segregation

Oct 29, 2007

Chromosomes are duplicated before they are segregated in equal parts to daughter-cells during cell division. An important regulator of this chromosome-separation is the "chromosomal passenger complex", a protein ...

Scientists deconstruct cell division

Feb 08, 2009

The last step of the cell cycle is the brief but spectacularly dynamic and complicated mitosis phase, which leads to the duplication of one mother cell into two daughter cells. In mitosis, the chromosomes ...

Recommended for you

Researchers successfully clone adult human stem cells

Apr 18, 2014

(Phys.org) —An international team of researchers, led by Robert Lanza, of Advanced Cell Technology, has announced that they have performed the first successful cloning of adult human skin cells into stem ...

Researchers develop new model of cellular movement

Apr 18, 2014

(Phys.org) —Cell movement plays an important role in a host of biological functions from embryonic development to repairing wounded tissue. It also enables cancer cells to break free from their sites of ...

For resetting circadian rhythms, neural cooperation is key

Apr 17, 2014

Fruit flies are pretty predictable when it comes to scheduling their days, with peaks of activity at dawn and dusk and rest times in between. Now, researchers reporting in the Cell Press journal Cell Reports on April 17th h ...

User comments : 0

More news stories

Biologists help solve fungi mysteries

(Phys.org) —A new genetic analysis revealing the previously unknown biodiversity and distribution of thousands of fungi in North America might also reveal a previously underappreciated contributor to climate ...

Researchers successfully clone adult human stem cells

(Phys.org) —An international team of researchers, led by Robert Lanza, of Advanced Cell Technology, has announced that they have performed the first successful cloning of adult human skin cells into stem ...

NASA's space station Robonaut finally getting legs

Robonaut, the first out-of-this-world humanoid, is finally getting its space legs. For three years, Robonaut has had to manage from the waist up. This new pair of legs means the experimental robot—now stuck ...

Ex-Apple chief plans mobile phone for India

Former Apple chief executive John Sculley, whose marketing skills helped bring the personal computer to desktops worldwide, says he plans to launch a mobile phone in India to exploit its still largely untapped ...

Filipino tests negative for Middle East virus

A Filipino nurse who tested positive for the Middle East virus has been found free of infection in a subsequent examination after he returned home, Philippine health officials said Saturday.

Egypt archaeologists find ancient writer's tomb

Egypt's minister of antiquities says a team of Spanish archaeologists has discovered two tombs in the southern part of the country, one of them belonging to a writer and containing a trove of artifacts including reed pens ...

Health care site flagged in Heartbleed review

People with accounts on the enrollment website for President Barack Obama's signature health care law are being told to change their passwords following an administration-wide review of the government's vulnerability to the ...