Williams Jaime M, Ouenzar Faissal, Lemon Laramie D, Chartrand Pascal, Bertuch Alison A
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030.
Department of Biochemistry, Université de Montréal, Montréal, Québec, Canada H3C 3J7.
Genetics. 2014 Aug;197(4):1123-36. doi: 10.1534/genetics.114.164707. Epub 2014 May 30.
Telomere length is tightly regulated in cells that express telomerase. The Saccharomyces cerevisiae Ku heterodimer, a DNA end-binding complex, positively regulates telomere length in a telomerase-dependent manner. Ku associates with the telomerase RNA subunit TLC1, and this association is required for TLC1 nuclear retention. Ku-TLC1 interaction also impacts the cell-cycle-regulated association of the telomerase catalytic subunit Est2 to telomeres. The promotion of TLC1 nuclear localization and Est2 recruitment have been proposed to be the principal role of Ku in telomere length maintenance, but neither model has been directly tested. Here we study the impact of forced recruitment of Est2 to telomeres on telomere length in the absence of Ku's ability to bind TLC1 or DNA ends. We show that tethering Est2 to telomeres does not promote efficient telomere elongation in the absence of Ku-TLC1 interaction or DNA end binding. Moreover, restoration of TLC1 nuclear localization, even when combined with Est2 recruitment, does not bypass the role of Ku. In contrast, forced recruitment of Est1, which has roles in telomerase recruitment and activation, to telomeres promotes efficient and progressive telomere elongation in the absence of Ku-TLC1 interaction, Ku DNA end binding, or Ku altogether. Ku associates with Est1 and Est2 in a TLC1-dependent manner and enhances Est1 recruitment to telomeres independently of Est2. Together, our results unexpectedly demonstrate that the principal role of Ku in telomere length maintenance is to promote the association of Est1 with telomeres, which may in turn allow for efficient recruitment and activation of the telomerase holoenzyme.
在表达端粒酶的细胞中,端粒长度受到严格调控。酿酒酵母Ku异二聚体是一种DNA末端结合复合体,以端粒酶依赖的方式正向调控端粒长度。Ku与端粒酶RNA亚基TLC1结合,这种结合是TLC1在细胞核内保留所必需的。Ku-TLC1相互作用还影响端粒酶催化亚基Est2与端粒的细胞周期调控结合。TLC1核定位的促进和Est2募集被认为是Ku在维持端粒长度中的主要作用,但这两种模型都未得到直接验证。在这里,我们研究了在Ku无法结合TLC1或DNA末端的情况下,将Est2强制募集到端粒上对端粒长度的影响。我们发现,在没有Ku-TLC1相互作用或DNA末端结合的情况下,将Est2拴系到端粒上并不能促进有效的端粒延长。此外,即使与Est2募集相结合,TLC1核定位的恢复也不能绕过Ku的作用。相反,在没有Ku-TLC1相互作用、Ku DNA末端结合或完全没有Ku的情况下,将在端粒酶募集和激活中起作用的Est1强制募集到端粒上可促进有效的和渐进的端粒延长。Ku以TLC1依赖的方式与Est1和Est2结合,并独立于Est2增强Est1募集到端粒上。总之,我们的结果出乎意料地表明,Ku在维持端粒长度中的主要作用是促进Est1与端粒的结合,这反过来可能允许端粒酶全酶的有效募集和激活。