Navigation Links
Scientists discover how chromosomes keep their loose ends loose
Date:2/6/2013

LA JOLLA, CA February 6, 2013 We take it for granted that our chromosomes won't stick together, yet this kind of cellular disaster would happen constantly were it not for a protein called TRF2. Now, scientists at The Scripps Research Institute (TSRI) have discovered key details of how TRF2 performs this crucial chromosome-protecting function. The finding represents a significant advance in cell biology and also has implications for our understanding of cancer and the aging process.

"Cells tend to interpret their chromosome ends as sites of DNA damage, and without TRF2, they would attempt to 'repair' these sites by fusing different chromosomes together," said TSRI Assistant Professor Eros Lazzerini Denchi. "The prevailing view has been that TRF2 has a passive role in hiding chromosome ends from the DNA repair machinery, but we found that it also actively suppresses the repair response."

Lazzerini Denchi is the corresponding author of the new study, which is reported in an Advance Online Publication of the journal Nature on February 6, 2013.

A Protective Cap

TRF2 is part of a protective protein cap localized at the ends of chromosomes, the telomeres. Telomeres shorten with every cellular division, and when they become too shortin aged organisms, for exampleTRF2 is no longer able to localize at chromosome ends. In such cases, chromosome ends become exposed and the DNA repair response is liable to knit uncapped chromosomes to each other. This action results in strings of chromosomes fused together that are unstable and can lead to cell death or, in some cases, to uncontrolled growth leading to cancer.

In 2007, as a postdoctoral researcher at The Rockefeller University, Lazzerini Denchi found that TRF2 works in part by blocking a particular signaling pathway in the DNA damage response. In the new study, he and his laboratory colleagues at TSRI have explored TRF2's functions in more detail.

"We found that TRF2 uses a two-step mechanism to protect chromosome ends," said Keiji Okamoto, a postdoctoral fellow in Lazzerini Denchi's laboratory who was the lead author of the new study.

TRF2 is a complex protein with four functional domains (regions). Okamoto probed the specific functions of these four domains by creating artificial TRF2-like proteinsin which one or more functional domains were replaced with non-functional "dummy" domains. By studying how these artificial TRF2s functioned in cells, he could determine the separate functions of each individual domain.

Uncovering Distinct Roles

Two of these domains turned out to have distinct roles in suppressing the DNA damage response. "One domain, called TRFH, blocks localization of the DNA damage factor γH2AX, the initial step in the DNA response pathway," said Okamoto. It may do so by inducing a structural change in telomeres that hides it from the DNA damage machinery. A distinct region of TRF2, which Okamoto dubbed iDDR (inhibitor of the DNA damage response pathway), independently and actively suppresses the transduction of the DNA damage signal downstream of γH2AX.

Okamoto and colleagues found that the iDDR region works in part by recruiting an enzymatic activity associated with the tumor suppressor protein BRCA1. Defects in BRCA1 lead to DNA misrepairs, genomic instability and a sharp rise in cancer risk. (Certain BRCA1 mutations bring a greater than 50-percent lifetime risk of breast or ovarian cancer.) This new finding hints that BRCA1 defects may result in defects in telomere protection, too.

Lazzerini Denchi, Okamoto and their colleagues now plan to explore TRF2's functions and protein partners in further detail, in cell studies and in transgenic mice. "We want to address the BRCA1 connection more thoroughly, too, for example, to determine the importance of its association with telomeres in preventing tumors," Lazzerini Denchi said.


'/>"/>

Contact: Mika Ono
mikaono@scripps.edu
858-784-2052
Scripps Research Institute
Source:Eurekalert  

Related medicine news :

1. Meeting: Scientists to explore 60 topical issues related to human health and the environment
2. Scientists debate CDC recommendations during meningitis outbreak
3. Scientists discover protein that allows safe recycling of iron from old red blood cells
4. MU scientists build harness for powerful radiation cancer therapy
5. Monell scientists identify elusive taste stem cells
6. American Association of Radon Scientists and Technologists (AARST) Releases Nation's First Standard for Mitigating Radon (Radioactivity) in Multifamily Buildings
7. Scientists Find Clue to Aging Reversal in Mice
8. Leading researchers warn of brain drain as scientists struggle to find funding
9. UNC scientists unveil a superbugs secret to antibiotic resistance
10. Scientists learn more about how inhibitory brain cells get excited
11. New target to stop cancers spread discovered by Georgia State scientists
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
Scientists discover how chromosomes keep their loose ends loose
(Date:2/13/2016)... ... February 13, 2016 , ... Valentine’s Day is nearly upon us, ... big day. A great outfit, flawless hair, and a sparkling personality are all well ... themselves to a night at home with Rover. (Actually, man’s best friend might not ...
(Date:2/13/2016)... ... ... individuals looking to lead a healthy lifestyle have decreased carbohydrate consumption and increased their ... delved into this niche allowing those giving up their beloved pasta a chance to ... of protein and only 7 grams of carbohydrates per 50 gram serving--a ratio that ...
(Date:2/13/2016)... ... February 13, 2016 , ... The producers of Enterprises TV ... , The increasingly modern world of instantaneous consumption proves very convenient for businesses. ... such as oil and coal, which pollutes our air, water, and soil. It can ...
(Date:2/13/2016)... ... 13, 2016 , ... Christie Medical Holdings, Inc. presented the ... VeinViewer® Vision vein finder for the nursing school simulation lab. This ... draw blood, combining technology with traditional technique. , “VeinViewer is a wonderful new ...
(Date:2/13/2016)... Montreal, Canada (PRWEB) , ... February 13, 2016 , ... ... best foot forward. They’ll groom themselves to perfection, go out of their way to ... their date – just take a look at any online dating profile. , ...
Breaking Medicine News(10 mins):
(Date:2/12/2016)... SAO PAULO , Feb. 12, 2016 /PRNewswire/ ... has commenced a cash tender offer (the "Tender ... U.S.$312.6 million outstanding aggregate principal amount of its ... P5246AAF0 and ISIN Nos. US44915JAA88/ USP5246AAF05) (the "Notes"). ... also soliciting (the "Consent Solicitation") consents (the "Consents") ...
(Date:2/12/2016)... , February 12, 2016 /PRNewswire/ ... nicht anders vermerkt)   http://www.sedar.com ... http://www.telestatherapeutics.com abrufbar.    --> ... des Unternehmens http://www.telestatherapeutics.com abrufbar.    ... (TSX:TST; PNK:BNHLF) veröffentlichte heute seinen Konzernabschluss des ...
(Date:2/12/2016)... HOUSTON , Feb. 12, 2016  Memorial Hermann ... center Dwight Howard to bring a one-of-a-kind ... Hospital . Using cutting-edge technologies such as 360-degree video ... kids both virtually, then literally – giving the patients ... – and it was all caught on video ...
Breaking Medicine Technology: