Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Enzyme crystal structure reveals ’unexpected’ genome repair functions

10.04.2006
New discovery could help improve some forms of chemotherapy
The study is being published in an advance online version of the journal Molecular Cell.

The research looked at XPB helicase from an archaea, a single cell organism similar to bacteria. Helicases are enzymes that unwind or separate the strands of the nucleic acid double helix, an action that is critical to transcription and nucleotide excision repair (NER), as well as other cell processes.

"XPB was initially identified as the gene responsible for NER defects in xeroderma pigmentosum patients, who are hypersensitive to light and have a dramatically increased risk of skin cancer," says John A. Tainer, a professor at Scripps Research and its Skaggs Institute for Chemical Biology who led the study. "This reflects the fact that XPB plays a key role in unwinding damaged DNA during NER, which removes a broad spectrum of DNA lesions, including those caused by exposure to ultraviolet light."

DNA needs constant repair because of the damage from a variety of sources that occurs to its base pairs of nucleotides. It is estimated that in every human cell more than 10,000 DNA bases are repaired each day, making NER critically important for cell survival and protection against mutations. NER is a critical defense mechanism that removes DNA lesions caused by the mutating effects of sunlight (ultraviolet light) and toxic chemicals.

In addition, NER is critical to the success of the anticancer drug cisplatin, since cisplatin works by initiating the process of DNA repair, in turn activating apoptosis or programmed cell death when the repair process fails. "Because chemotherapeutic agents like the chemotherapy drug cisplatin and radiation therapy work by essentially damaging DNA, any new understanding of the DNA repair mechanism could mean potential improvements in the treatment of cancer," Tainer says.

Prior to this study, there were no specific models for how XPB acts in DNA separation either to initiate transcription or to begin NER. There were also no models for the role that XPB, which is an essential subunit of Transcription Factor IIH (TFIIH) functional assembly complex, might play in changing conformations for TFIIH’s alternate roles in either transcription or DNA repair.

The XPB crystal structures developed by the researchers identified unexpected functional domains for XPB that, according to the study, help "address key questions about XPB structure-function relationships for transcription and nucleotide excision repair."

Research Associate Li Fan of Scripps Research, the first author of the study, adds, "We were surprised when we found that XPB contains a domain structurally similar to the mismatch recognition domain of a bacterial DNA repair protein MutS. MutS helps recognize and repair mismatched DNA in E. coli. These two proteins have little sequence similarity. Biochemical assays following this discovery indicate that this domain allows XPB to interact with damaged DNA and enhances its unwinding activity on damaged DNA."

The report suggests that unknown protein and DNA interactions at transcription sites activate XPB within the TFIIH complex to allow it to start the DNA unwinding process.

"Even though TFIIH does not act directly in initial damage recognition, the interaction of XPB with the DNA lesion suggests that XPB plays a role in switching TFIIH from transcription mode to NER," Tainer says. "The structural biochemistry of XPB that we discovered shows an unexpected molecular mechanism by which XPB plays a key role in determining exactly how TFIIH functions, whether in transcription or repair mode."

Keith McKeown | EurekAlert!
Further information:
http://www.scripps.edu

More articles from Life Sciences:

nachricht Repairing damaged hearts with self-healing heart cells
22.08.2017 | National University Health System

nachricht Biochemical 'fingerprints' reveal diabetes progression
22.08.2017 | Umea University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

Cholesterol-lowering drugs may fight infectious disease

22.08.2017 | Health and Medicine

Meter-sized single-crystal graphene growth becomes possible

22.08.2017 | Materials Sciences

Repairing damaged hearts with self-healing heart cells

22.08.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>