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Jan 9, 2014

Enzyme Reverses Stalled Transcription Machinery to Aid DNA Repair

Enzyme Reverses Stalled Transcription Machinery to Aid DNA Repair

In a new DNA repair model, RNA polymerase patrols tracks of double-stranded DNA and stalls over damaged areas. An enzyme called UvrD helicase pulls the blocked RNA polymerase off the break, exposing the DNA lesion to repair. [NYU Langone Medical Center]

  • Rather like a train halted by damaged rails is hauled away, the better to expose the rails to repair crews, RNA polymerase that is snagged by a faulty stretch of DNA can be pulled backwards by an enzyme, a transcription elongation factor with helicase/translocase activity. This enzyme appears to play an essential role in nucleotide excision repair, helping RNA polymerase backtrack when necessary, facilitating its transcriptional role, and even enabling it to serve a damage-scanning function.

    That RNA polymerase may benefit from this kind of assistance was deduced by researchers at New York University’s Langone Medical Center. They found that UvrD, an enzyme in Escherichia coli, binds RNA polymerase during transcription elongation and, by virtue of its helicase/translocase activity, forces RNA polymerase to slide backward along DNA. By inducing backtracking, UvrD exposes DNA lesions shielded by blocked RNA polymerase, allowing nucleotide excision repair enzymes to gain access to sites of damage.

    These findings were published in the January 8 issue of Nature, in a paper entitled “UvrD facilitates DNA repair by pulling RNA polymerase backwards.” They have broad relevance because they describe a repair mechanism that is widely shared by organisms ranging from bacteria to humans. UvrD’s human analog, a protein known as XPB, is needed to prevent a range of serious disorders. Inherited defects in the gene that encodes for XPB have been linked to conditions such as xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy.

    According to Evgeny Nudler, Ph.D., the researcher who headed up the NYU team, a smoothly operating repair mechanism means “means fewer mutations, which also means slower aging, less cancer, and many other pathologies.”

    The NYU team, together with colleagues in Russia, used a battery of biochemical and genetic experiments to directly link UvrD to RNA polymerase and to demonstrate that UvrD’s pulling activity is essential for DNA repair. The researchers also found, as they indicated in their article, that “the elongation factor NusA cooperates with UvrD in coupling transcription to DNA repair.” UvrD and NusA work with each other, “promoting backtracking and recruiting nucleotide excision repair enzymes to exposed lesions.”

    The researchers contrasted their backtracking mechanism with another repair mode, one in which Mfd, a DNA translocase, binds to a stalled elongation complex through the beta subunit of RNA polymerase and dislodges the complex by “pushing” it forward. Unlike Mfd, wrote the researchers, “UvrD facilitates nucleotide excision repair by pulling RNA polymerase backward from the DNA lesion without causing termination.”

    According to Dr. Nudler, his team's study offers a convincing justification for a puzzling phenomenon known as pervasive transcription, which he calls “one of the most enigmatic and debated subjects of molecular biology.” The question, he says, boils down to this: Why do RNA polymerases transcribe most of the genome within humans and other organisms, converting vast stretches of DNA to RNA, when only a tiny fraction of those resulting RNA transcripts will ever prove useful? Isn't that RNA polymerase activity a waste of energy and resources?

    "Our results imply that a major role of RNA polymerase is to patrol the genome for DNA damage," he says. "This is the only molecular machine that is capable of continuously scanning the chromosomes for virtually any deviation from the canonical four bases in the template strand: A, T, G and C." The polymerase's extensive transcription activity, then, might be well worth the effort if its continuous vigilance also ensures that any DNA damage gets fixed through the assistance of the pulling factors and other collaborators.



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