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."