Functional subdomain in the ankyrin domain of Tankyrase 1 required for poly(ADP-ribosyl)ation of TRF1 and telomenre elongation
Functional subdomain in the ankyrin domain of Tankyrase 1 required for poly(ADP-ribosyl)ation of TRF1 and telomenre elongation
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DOI：
10.1128/mcb.24.5.1944-1955.2004
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发表时间：
2004-03-01
影响因子：
5.3
通讯作者：
Tsuruo, T
中科院分区：
文献类型：
--
作者：
Seimiya, H;Muramatsu, Y;Tsuruo, T
在人类细胞中，端粒酶引起的端粒延长被端粒蛋白 TRF1 顺式抑制。端锚聚合酶 1 通过其锚蛋白结构域结合 TRF1，并对其进行聚 (ADP-核糖基) 化。端粒酶阳性细胞中端锚聚合酶 1 的过度表达会从端粒释放 TRF1，导致端粒伸长。端锚聚合酶 I 锚蛋白结构域分为五个保守的子结构域，ARC（锚蛋白重复簇）I 至 V。在这里，我们研究了 ARC 的生物学意义。首先，每个 ARC 作为 TRF1 的独立结合位点。其次，ARC II 至 V 识别 TRF1 的 N 端酸性结构域，而 ARC I 结合 TRF1 的同二聚化结构域和 Myb 样结构域之间的离散位点。通过删除或点突变使 C 端 ARC、ARC V 中的 TRF1 结合失活，显着降低端锚聚合酶 1 聚（ADP-核糖基）化 TRF1、从端粒释放 TRF1 和延长端粒的能力。相比之下，通过点突变失活的其他 ARC、ARC II 和/或 IV 仍然保留坦科聚合酶 1 的生物学功能。另一方面，ARC V 本身不足以延长端粒，这表明多个 ARC 具有结构作用。这项工作提供了证据，证明特定的 ARC-TRF1 相互作用在坦科聚合酶 1 的基本催化功能中发挥作用。
In human cells, telomere elongation by telomerase is repressed in cis by the telomeric protein TRF1. Tankyrase 1 binds TRF1 via its ankyrin domain and poly(ADP-ribosyl)ates it. Overexpression of tankyrase 1 in telomerase-positive cells releases TRF1 from telomeres, resulting in telomere elongation. The tankyrase I ankyrin domain is classified into five conserved subdomains, ARCs (ankyrin repeat clusters) I to V. Here, we investigated the biological significance of the ARCs. First, each ARC worked as an independent binding site for TRF1. Second, ARCs II to V recognized the N-terminal acidic domain of TRF1 whereas ARC I bound a discrete site between the homodimerization and the Myb-like domains of TRF1. Inactivation of TRF1 binding in the C-terminal ARC, ARC V, either by deletion or point mutation, significantly reduced the ability of tankyrase 1 to poly(ADP-ribosyl)ate TRF1, release TRF1 from telomeres, and elongate telomeres. In contrast, other ARCs, ARC II and/or IV, inactivated by point mutations still retained the biological function of tankyrase 1. On the other hand, ARC V per se was not sufficient for telomere elongation, suggesting a structural role for multiple ARCs. This work provides evidence that specific ARC-TRF1 interactions play roles in the essential catalytic function of tankyrase 1.