Paf1 Counteracts transcriptional arrest to maintain rDNA stability during pol I elongation.

Zijun Zhong, Masaaki Yokoyama, Takehiko Kobayashi

Laboratory of Genome Regeneration, Institute for Quantitative Biosciences (IQB), The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan; Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.Laboratory of Genome Regeneration, Institute for Quantitative Biosciences (IQB), The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan; Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. · pubmed

Paper

Abstract

Genomic instability drivers of senescence and carcinogenesis. The ribosomal RNA gene (rDNA) locus in budding yeast provides an excellent model to study these processes. Because of its highly repetitive structure and the gene amplification system that maintains its copy number, rDNA represents one of the most unstable regions in the genome. Here, we demonstrate that the integrity of rDNA transcription is essential for maintaining genomic stability and lifespan. Loss of Paf1, an elongation factor associated with RNA polymerase, reduces rDNA transcription, stability, and lifespan. In paf1 mutants, R-loops accumulate within the rDNA, generating single-stranded regions prone to breakage. This triggers double-strand breaks at replication forks, leading to rDNA copy number variation and DNA fragmentation. Torsional stress generated by R-loops also results in the accumulation of Top1. These abnormalities are partially dependent on canonical amplification recombination pathways, including those regulated by replication fork blocking and non-coding transcription.

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Research summary

The study demonstrates that the elongation factor Paf1 maintains rDNA stability by preventing R-loop accumulation, and its loss leads to genomic instability and reduced lifespan in yeast. This work provides a mechanistic link between transcriptional fidelity at repetitive loci and organismal aging, contributing to the fundamental understanding of genomic instability as a driver of senescence.

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