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October 17, 2014

"Gangway!" in the Genome Prevents Transcription/Replication Wreckage

Dicer helps prevent collisions between transcription and replication machinery. In cells that lack Dicer, DNA damage accumulates (yellow spots), leading to DNA rearrangements. [CSHL/Jie Ren and Stephen Hearn]

  • The genome is a crowded, busy place, particularly along stretches containing genes required for basic survival. In these regions, transcription is nearly constant, which means that DNA’s transcriptional machinery is seldom absent. So what happens during cell division, when DNA’s replication machinery comes rumbling down the line? How are collisions between transcriptional machinery and replication machinery avoided?

    Actually, sometimes collisions are not avoided, and the genome sustains damage of the sort associated with aging and diseases such as cancer. Still, it is curious that collisions don’t happen more frequently.

    To explain how the genome remains stable despite the comings and goings of DNA machines, researchers at Cold Spring Harbor Laboratory (CSHL) investigated a protein called Dicer. Best known for its role in selectively silencing genes via a process called RNA interference (RNAi), Dicer has also been known to resolve transcription/replication conflicts in isolated areas of the genome where genes are being silenced.

    Dicer, the researchers reasoned, might also promote stability throughout the genome. The researchers, led by Robert Martienssen, Ph.D., a CSHL professor and Howard Hughes Medical Institute investigator, used a genome-wide approach in the fission yeast S. pombe to establish that “Dcr1, but not other components of the canonical RNAi pathway, promotes the release of Pol II from the 3′ end of highly transcribed genes, and, surprisingly, from antisense transcription of rRNA and tRNA genes, which are normally transcribed by Pol I and Pol III.”

    In other words, Dicer appears to usher transcriptional machinery out of the way of replication machinery. This result appeared October 16 in the journal Cell, in an article entitled, “Dicer Promotes Transcription Termination at Sites of Replication Stress to Maintain Genome Stability.”

    “These Dcr1-terminated loci correspond to sites of replication stress and DNA damage, likely resulting from transcription-replication collisions,” wrote the authors. “At the rDNA loci, release of Pol II facilitates DNA replication and prevents homologous recombination, which would otherwise lead to loss of rDNA repeats, especially during meiosis.”

    The researchers speculated that Dcr1-mediated transcription termination could account for widespread regulation of genome stability by nuclear RNAi not just in yeast, but in higher eukaryotes. For example, the researchers noted that other investigators have shown that mutations in dicer are associated with an increased risk of tumor formation.

    "It may be that Dicer's role in cancer is to protect the genome by preventing collisions between transcription and replication," noted Dr. Martienssen.

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