Protein's essential role in repairing damaged cells revealed

January 6, 2009
Protein's essential role in repairing damaged cells revealed

Enlarge

Pictured are study authors David O. Ferguson, M.D., Ph.D., and Jeffrey Buis. Credit: University of Michigan

University of Michigan researchers have discovered that a key protein in cells plays a critical role in not one, but two processes affecting the development of cancer.

"Most proteins involved in responding to DNA damage that can cause cancer either help detect the damage and warn the rest of the cell, or help repair the damage," says David O. Ferguson, M.D., Ph.D., the study's lead author. Ferguson is an assistant professor of pathology at the U-M Medical School and a member of U-M's Comprehensive Cancer Center.

Prior research has shown that the protein, Mre11, functioned as a "gatekeeper" to signal injury to the cell and prevent damaged cells from proliferating. Now, Ferguson and colleagues have discovered that in mammals, a function of the Mre11 protein also serves as a "caretaker," by repairing DNA.

Their findings, published in the journal Cell, could have important implications for cancer treatment by someday allowing oncologists to predict a tumor's sensitivity to radiation and other therapies, making it more vulnerable to treatment.

Under normal circumstances, the body's cells grow, divide and eventually die. When something damages a healthy cell's DNA -- such as radiation or exposure to a toxin -- a multiprotein complex steps in to repair the breakage and activate other fundamental cellular processes.

The MRN complex, comprised of the Mre11, Rad50 and NBS1 proteins, senses DNA damage, known as double-strand breaks, within the cell. The complex then transmits that information to an enzyme called the ATM (ataxia-telangiectasia mutated) checkpoint kinase.

The ATM kinase controls the cell's response to double-strand breaks, and slows cell growth to give the cell opportunities to repair them, says Ferguson.

When the MRN complex doesn't work properly, inherited human neurological diseases, such as ataxia-telangiectasia-like syndrome and Nijmegen breakage syndrome, result. Both feature MRN mutations and significantly predispose a person to immunodeficiency and cancer.

What Ferguson and colleagues discovered is that Mre11 not only senses and communicates damage, it also repairs DNA double-strand breaks by acting as a nuclease, an enzyme that modifies and processes the broken DNA ends.

Research details

The researchers generated mouse models to examine the exact role of Mre11 in the MRN complex. They engineered two mouse strains, one in which Mre11 was disabled completely, and one in which only a single amino acid change was made.

What surprised researchers the most was that making that change to a single amino acid in Mre11 caused consequences as severe as when they eliminated the entire MRN complex.

Taking out the amino acid in Mre11 responsible for nuclease activity caused the mice to develop growth defects, chromosomal abnormalities and sensitivity to DNA-damaging agents. Therefore, researchers could say that the nuclease, or repair, activity of Mre11 proves critical for both MRN function and stability of the genetic material of the organism.

"First, Mre11 signals to the cell by activating the kinase, but it also acts in the repair of double-strand breaks via the nuclease functions. Therefore, it prevents the two individual steps that lead to cancer," Ferguson says.

Implications

The work, called "virtuoso cell engineering" in a Cell preview article, holds particular promise for identifying mutations associated with many cancers.

"What's emerging in the literature from large-scale screening studies of human tumors is that Mre11 may be frequently mutated in certain cancers," Ferguson says.

"This may have implications for diagnoses because tumors associated with different mutations may have different prognoses and respond to different therapies," he says. In particular, mutations in Mre11 may predict how sensitive or resistant a particular tumor will be to treatments with DNA-damaging agents.

"The fact that we have now separated the functions of DNA repair from the checkpoint functions means we may have identified a target that can sensitize tumors to radiation and chemotherapeutic agents used in treating cancer."

Reference: Cell, Vol. 135, Issue 1, pp. 85-96

Source: University of Michigan

3.3 /5 (4 votes)  

Filter


Move the slider to adjust rank threshold, so that you can hide some of the comments.


Display comments: newest first

E_L_Earnhardt
Jan 07, 2009

Rank: not rated yet
I would interject that the CAUSE of damage within the cell could be related to EXCESS ENERGY! (Defined as excess speed and spin of electrons or "HEAT") If by sterile water drip or ice pack the heat were reduced mitosis would slow or stop!
Rank 3.3 /5 (4 votes)
Relevant PhysicsForums posts

More news stories

The power of estrogen -- male snakes attract other males

A new study has shown that boosting the estrogen levels of male garter snakes causes them to secrete the same pheromones that females use to attract suitors, and turned the males into just about the sexiest ...

Biology / Plants & Animals

created 12 hours ago | popularity 4.8 / 5 (5) | comments 0 | with audio podcast

Grass to gas: Researchers' genome map speeds biofuel development

Researchers at the University of Georgia have taken a major step in the ongoing effort to find sources of cleaner, renewable energy by mapping the genomes of two originator cells of Miscanthus x giganteus, a large perenn ...

Biology / Biotechnology

created 9 hours ago | popularity 3.8 / 5 (5) | comments 0 | with audio podcast

Experts reveal how plants don't get sunburn

(PhysOrg.com) -- Experts at the University of Glasgow have discovered how plants survive the harmful rays of the sun.

Biology / Cell & Microbiology

created 12 hours ago | popularity 4.7 / 5 (3) | comments 0 | with audio podcast

Miami battling invasion of giant African snails

No one knows how they got there. But an invasion of African giant snails has southern Florida in a panic over potential crop damage, disease and general yuckiness surrounding the slimy gastropods.

Biology / Ecology

created 16 hours ago | popularity 4 / 5 (1) | comments 4

Protein libraries in a snap

(PhysOrg.com) -- A Rice University undergraduate will depart with not only a degree but also a possible patent for his invention of an efficient way to create protein libraries, an important component of biomolecular ...

Biology / Cell & Microbiology

created 15 hours ago | popularity 4.8 / 5 (4) | comments 0 | with audio podcast


Google users warned of threat to smartphone wallets

Users of Google smartphone wallets were being warned on Friday that there is a way to crack pass codes intended to thwart thieves from going on illicit shopping sprees.

Anonymous knocks CIA website offline (Update)

The website of the Central Intelligence Agency was inaccessible on Friday after the hacker group Anonymous claimed to have knocked it offline.

Complex wiring of the nervous system may rely on a just a handful of genes and proteins

Researchers at the Salk Institute have discovered a startling feature of early brain development that helps to explain how complex neuron wiring patterns are programmed using just a handful of critical genes. ...

New error-correcting codes guarantee the fastest possible rate of data transmission

Error-correcting codes are one of the triumphs of the digital age. They’re a way of encoding information so that it can be transmitted across a communication channel — such as an optical fiber o ...

Humans may have helped the decline of African rainforests 3000 years ago

(PhysOrg.com) -- Large areas of rainforests in Central Africa mysteriously disappeared over three thousand years ago, to be replaced by savannas. The prevailing theory has been that the cause was a change ...

Putting the squeeze on planets outside our solar system

(PhysOrg.com) -- Using high-powered lasers, scientists at Lawrence Livermore National Laboratory and collaborators discovered that molten magnesium silicate undergoes a phase change in the liquid state, abruptly ...