Rap1 affects the length and heterogeneity of human telomeres
Rap1 affects the length and heterogeneity of human telomeres
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DOI：
10.1091/mbc.e03-06-0403
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发表时间：
2003-12-01
影响因子：
3.3
通讯作者：
de Lange, T
中科院分区：
文献类型：
--
作者：
Li, BB;de Lange, T
端粒长度部分由顺式作用负调节因子控制，这些负调节因子限制端粒酶延长端粒。在芽殖酵母中，主要的端粒长度调节因子 scRap1 与端粒 DNA 结合，并抑制端粒顺式伸长。由于人类 Rap1 直系同源物 hRap1 不直接与端粒 DNA 结合，而是通过 TRF2 招募到端粒，因此我们检查了其在端粒长度控制中的作用。这些数据与 hRap1 是端粒长度的负调节因子一致，表明功能保守。删除图谱证实 hRap1 通过其 C 末端与 TRF2 的相互作用与端粒相连。 hRap1 缺失突变体的端粒长度表型表明 BRCT 和 Myb 结构域都是参与端粒长度调节的蛋白质相互作用结构域。相比之下，scRap1 通过其 Myb 结构域与端粒结合，并使用其 C 末端来招募端粒长度调节因子 Rif1 和 Rif2。总之，我们的数据表明，尽管 Rap1 在端粒上的作用在很大程度上是保守的，但 Rap1 的结构域在真核进化过程中经历了广泛的功能变化。令人惊讶的是，缺乏 BRCT 结构域的 hRap1 等位基因降低了人类端粒的异质性，表明 hRap1 在端粒长度分布的调节中也发挥着作用。
Telomere length is controlled in part by cis-acting negative regulators that limit telomere extension by telomerase. In budding yeast, the major telomere length regulator scRap1 binds to telomeric DNA and acts to inhibit telomere elongation in cis. Because the human Rap1 ortholog hRap1 does not bind to telomeric DNA directly but is recruited to telomeres by TRF2, we examined its role in telomere length control. The data are consistent with hRap1 being a negative regulator of telomere length, indicating functional conservation. Deletion mapping confirmed that hRap1 is tethered to telomeres through interaction of its C terminus with TRF2. The telomere length phenotypes of hRap1 deletion mutants implicated both the BRCT and Myb domain as protein interaction domains involved in telomere length regulation. By contrast, scRap1 binds to telomeres with its Myb domains and uses its C terminus to recruit the telomere length regulators Rif1 and Rif2. Together, our data show that although the role of Rap1 at telomeres has been largely conserved, the domains of Rap1 have undergone extensive functional changes during eukaryotic evolution. Surprisingly, hRap1 alleles lacking the BRCT domain diminished the heterogeneity of human telomeres, indicating that hRap1 also plays a role in the regulation of telomere length distribution.