Miller Kyle M, Ferreira Miguel Godinho, Cooper Julia Promisel
Cancer Research UK, London Research Institute, London, UK.
EMBO J. 2005 Sep 7;24(17):3128-35. doi: 10.1038/sj.emboj.7600779. Epub 2005 Aug 11.
Telomere protection and maintenance are accomplished through the coordinated actions of telomere-specific DNA binding proteins and their interacting partners. The fission yeast ortholog of human TRF1/2, Taz1, binds telomeric DNA and regulates numerous aspects of telomere function. Here, we ask which aspects of Taz1 function are mediated through its interacting proteins, Rap1 and Rif1. We demonstrate that rap1+ deletion phenocopies some, but not all, aspects of taz1Delta telomere dysfunction, while Rif1 exhibits a very different functional spectrum. Rap1 acts in a Taz1-dependent pathway to prevent chromosome end fusions and regulate telomeric 3' overhang formation, while Rif1 is dispensable for these functions. Telomerase inhibition by Taz1 is mediated by two separate pathways, one involving Rap1 and the other involving Rif1. In contrast, Taz1 is uniquely required to prevent chromosomal entanglements and missegregation at cold temperatures. Strikingly, while rap1+ deletion exacerbates the cold sensitivity of taz1Delta cells, rif1+ deletion restores full viability. Thus, Rap1 and Rif1 are each required for a subset of the functions of Taz1, but each acquires Taz1-independent functions in its absence. Furthermore, Taz1 can function independently of its known binding partners.
端粒的保护和维持是通过端粒特异性DNA结合蛋白及其相互作用伙伴的协同作用来实现的。人类TRF1/2在裂殖酵母中的直系同源物Taz1,结合端粒DNA并调节端粒功能的多个方面。在此,我们探究Taz1功能的哪些方面是通过其相互作用蛋白Rap1和Rif1介导的。我们证明,rap1 +缺失模拟了taz1Δ端粒功能障碍的一些但并非全部方面,而Rif1表现出非常不同的功能谱。Rap1在一条依赖Taz1的途径中发挥作用,以防止染色体末端融合并调节端粒3' 端悬突的形成,而Rif1对于这些功能是可有可无的。Taz1对端粒酶的抑制作用由两条独立的途径介导,一条涉及Rap1,另一条涉及Rif1。相比之下,在低温下防止染色体缠结和错误分离唯独需要Taz1。引人注目的是,虽然rap1 +缺失加剧了taz1Δ细胞的冷敏感性,但rif1 +缺失恢复了完全的活力。因此,Rap1和Rif1各自都是Taz1部分功能所必需的,但在其缺失时各自获得了不依赖Taz1的功能。此外,Taz1可以独立于其已知的结合伙伴发挥作用。