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!
Researchers uncover protein-based “cancer signature”
05.12.2016 | Universität Basel
The Nagoya Protocol Creates Disadvantages for Many Countries when Applied to Microorganisms
05.12.2016 | Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
05.12.2016 | Power and Electrical Engineering
05.12.2016 | Information Technology
05.12.2016 | Earth Sciences