PIF1 家族 DNA 解旋酶抑制 tRNA 基因处 R 环介导的基因组不稳定性。
PIF1 family DNA helicases suppress R-loop mediated genome instability at tRNA genes.
机构信息
Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, New Jersey 08544, USA.
Department of Human Genetics, University of Chicago, 920 E 58th St, Chicago, Illinois 60637, USA.
出版信息
Nat Commun. 2017 Apr 21;8:15025. doi: 10.1038/ncomms15025.
Saccharomyces cerevisiae encodes two Pif1 family DNA helicases, Pif1 and Rrm3. Rrm3 promotes DNA replication past stable protein complexes at tRNA genes (tDNAs). We identify a new role for the Pif1 helicase: promotion of replication and suppression of DNA damage at tDNAs. Pif1 binds multiple tDNAs, and this binding is higher in rrm3Δ cells. Accumulation of replication intermediates and DNA damage at tDNAs is higher in pif1Δ rrm3Δ than in rrm3Δ cells. DNA damage at tDNAs in the absence of these helicases is suppressed by destabilizing R-loops while Pif1 and Rrm3 binding to tDNAs is increased upon R-loop stabilization. We propose that Rrm3 and Pif1 promote genome stability at tDNAs by displacing the stable multi-protein transcription complex and by removing R-loops. Thus, we identify tDNAs as a new source of R-loop-mediated DNA damage. Given their large number and high transcription rate, tDNAs may be a potent source of genome instability.
酿酒酵母编码两种 Pif1 家族 DNA 解旋酶，Pif1 和 Rrm3。Rrm3 促进 tRNA 基因（tDNAs）处稳定蛋白复合物的 DNA 复制。我们发现了 Pif1 解旋酶的一个新作用：促进 tDNAs 处的复制和抑制 DNA 损伤。Pif1 结合多个 tDNAs，在 rrm3Δ 细胞中这种结合更高。在 pif1Δ rrm3Δ 细胞中，tDNAs 处的复制中间体和 DNA 损伤的积累高于 rrm3Δ 细胞。在这些解旋酶缺失的情况下，tDNAs 处的 DNA 损伤通过破坏不稳定的 R 环而得到抑制，而 Pif1 和 Rrm3 与 tDNAs 的结合在 R 环稳定时增加。我们提出，Rrm3 和 Pif1 通过置换稳定的多蛋白转录复合物和去除 R 环来促进 tDNAs 处的基因组稳定性。因此，我们确定 tDNAs 是 R 环介导的 DNA 损伤的新来源。鉴于它们的数量众多和转录率高，tDNAs 可能是基因组不稳定性的一个潜在来源。
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