Navigation Links
Protein plays unexpected role protecting chromosome tips
Date:8/13/2009

HOUSTON - A protein specialist that opens the genomic door for DNA repair and gene expression also turns out to be a multi-tasking workhorse that protects the tips of chromosomes and dabbles in a protein-destruction complex, a team lead by researchers at The University of Texas M. D. Anderson Cancer Center reports in the Aug. 13 edition of Molecular Cell.

"Instead of being a really important tool dedicated just to regulation of gene transcription, Gcn5 is more like a Swiss Army knife that performs different functions depending on what needs to be done in the cell," said senior author Sharon Dent, Ph.D., professor in M. D. Anderson's Department of Biochemistry and Molecular Biology.

The researchers document a chain of events that starts with depletion of Gcn5, which leads to decreased activity by another protein that protects yet a third protein from destruction. That last protein, TRF1, protects telomeres, dense structures at the end of chromosomes which, like the compressed plastic tips on the ends of a shoelace, keep the chromosome ends intact.

Variation in the gene that expresses the middle protein in this model, ubiquitin specific protease 22 (USP22), is part of an 11-gene signature associated with highly metastatic cancers and poor prognosis, the authors note.

"Our results indicate that the Gcn5 complex regulates not just gene transcription but also protein stability," Dent said. "They also suggest that the role of USP22 in highly aggressive cancers might be due to these new functions."

Telltale telomere damage

Chromosomes are made of DNA that is tightly intertwined with proteins called histones to form chromatin. Chromatin is a condensed structure that forms a natural barrier inhibiting access to DNA. Gcn5 was previously known for its role in a complex of proteins that loosens chromatin to allow access to DNA by the cell's DNA repair machinery and by transcription factors that launch the process of gene expression.

"Years ago a student in my lab found that mice deficient in Gcn5 died early during embryonic development," Dent said. "The reason they died, in part, was that telomeres were fusing together. There was no reason to think Gcn5 would have anything at all to do with telomeres, so these fusions were quite puzzling."

Clues for protein's role in metastatic cancer

While Dent and colleagues attacked the problem, a research group elsewhere discovered that USP22 is active in the same protein complex in which Gcn5 operates. USP22 protects proteins by pealing off ubiquitin molecules that attach to the proteins and mark them for destruction by the proteasome complex.

A literature review showed that TRF1 carries a ubiquitin mark that makes it vulnerable to degradation by the proteasome.

"TRF1 normally resides at the telomeres and tells the cell that this is a normal chromosome end and you should leave it alone," Dent said. "If you don't have enough TRF1, the cell now thinks these chromosomal ends are abnormal and tries to fix them when they shouldn't be fixed."

Putting it all together, the team hypothesized that USP22 protects telomeres by knocking ubiquitins off of TRF1, sparing it from destruction. "Our model is of a pathway in which depletion of Gcn5 reduces USP22 activity, causing greater TRF1 ubiquination, which leads to TRF1 destruction and that leads to telomere problems," Dent said.

In the Molecular Cell paper, the researchers show that depletion of Gcn5 leads to chromosomal fusion and damage in mouse embryonic cell lines and also reduces the level of TRF1. They then demonstrate that USP22 interacts with TRF1 and is required for that protein to remain stable. Additional experiments identified ubiquitin removal is the mechanism by which USP22 protects TRF1.

Dent and colleagues continue to look for new proteins and cellular processes that are impaired in cells lacking GCN5 or USP22. "There must be a reason why USP22 is over expressed in highly metastatic cancers and we are encouraged that we will be able to provide important clues for this process," Dent said.


'/>"/>

Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert  

Related medicine news :

1. Draining away brains toxic protein to stop Alzheimers
2. Penn study finds pro-death proteins required to regulate healthy immune function
3. New prion protein discovered by Canadian scientists may offer insight into mad cow disease
4. Emory researchers identify signaling protein for multiple myeloma
5. Human C-reactive protein regulates myeloma tumor cell growth and survival
6. Lowering Blood Protein Wont Help Kidney Patients
7. Blood protein detects lung cancer, even at earliest stage
8. Natural Protein Could Help Spot, Treat Liver Cancer
9. Heat shock proteins are co-opted for cancer
10. How adhesive protein causes malaria
11. Loss of gene leads to protein splicing and buildup of toxic proteins in neurons
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
Protein plays unexpected role protecting chromosome tips
(Date:4/28/2016)... , ... April 28, 2016 , ... La Sirena Foods ... one in Central America and is looking to grow their market share in the ... an exceptional brand as La Sirena Foods and indirectly with Otis ...
(Date:4/28/2016)... ... April 28, 2016 , ... ... today the open availability of a new CDISC standard, Clinical Trial Registry ... clinical trials. This innovative standard will make it possible to build applications ...
(Date:4/28/2016)... West Palm Beach, FL (PRWEB) , ... April 28, 2016 , ... ... time for the spring season. Smart pots are frequently used by professional organic farmers ... time for growers to order their supply of fabric pots. Our goal is to ...
(Date:4/28/2016)... ... April 28, 2016 , ... ... enterprise Data Center Infrastructure Management solutions, announces today the availability of its ... in the area of capacity management and optimization, providing new analytical capabilities ...
(Date:4/28/2016)... ... April 28, 2016 , ... USA Medical Card reminds us that May is National Stroke Awareness ... the fourth leading cause of death in the United States; someone has one every 40 ... them in individuals under 65 years old. A stroke is when blood flow to ...
Breaking Medicine News(10 mins):
(Date:4/26/2016)... Diplomat Pharmacy, Inc. (NYSE: DPLO) is pleased ... Pharm D., to Vice President of Education and Quality. ... will continue to lead and oversee Diplomat University, an ... and training to Diplomat employees and external professionals on ... also houses the quality assurance department, which focuses on ...
(Date:4/26/2016)... 2016 US demand for infection prevention ... percent annually to $27.6 billion in 2020.  Increasing ... decrease rates of healthcare-associated infections (HAIs) will boost ... services.  Although declining, the overall rate of certain ... set by the CDC.  Recent statistics indicate that ...
(Date:4/26/2016)... DUBLIN , April 26, 2016 ... "Financial Assessment and Credit Risk Analysis of the Biological ... This comprehensive report analyzes the financial assessment ... China . The report provides readers ... key topics all market participants should be aware of. ...
Breaking Medicine Technology: