Bandaria Jigar N, Qin Peiwu, Berk Veysel, Chu Steven, Yildiz Ahmet
Department of Physics, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Department of Physics, University of California, Berkeley, Berkeley, CA 94720, USA.
Cell. 2016 Feb 11;164(4):735-46. doi: 10.1016/j.cell.2016.01.036.
Telomeres, repetitive DNA sequences at chromosome ends, are shielded against the DNA damage response (DDR) by the shelterin complex. To understand how shelterin protects telomere ends, we investigated the structural organization of telomeric chromatin in human cells using super-resolution microscopy. We found that telomeres form compact globular structures through a complex network of interactions between shelterin subunits and telomeric DNA, but not by DNA methylation, histone deacetylation, or histone trimethylation at telomeres and subtelomeric regions. Mutations that abrogate shelterin assembly or removal of individual subunits from telomeres cause up to a 10-fold increase in telomere volume. Decompacted telomeres accumulate DDR signals and become more accessible to telomere-associated proteins. Recompaction of telomeric chromatin using an orthogonal method displaces DDR signals from telomeres. These results reveal the chromatin remodeling activity of shelterin and demonstrate that shelterin-mediated compaction of telomeric chromatin provides robust protection of chromosome ends against the DDR machinery.
端粒是位于染色体末端的重复DNA序列，通过端粒保护蛋白复合体免受DNA损伤反应（DDR）的影响。为了了解端粒保护蛋白如何保护端粒末端，我们使用超分辨率显微镜研究了人类细胞中端粒染色质的结构组织。我们发现，端粒通过端粒保护蛋白亚基与端粒DNA之间复杂的相互作用网络形成紧密的球状结构，而非通过端粒和亚端粒区域的DNA甲基化、组蛋白去乙酰化或组蛋白三甲基化。消除端粒保护蛋白组装或从端粒中去除单个亚基的突变会导致端粒体积增加多达10倍。解压缩的端粒积累DDR信号，并变得更容易被端粒相关蛋白接近。使用正交方法对端粒染色质进行重新压缩会将DDR信号从端粒中置换出来。这些结果揭示了端粒保护蛋白的染色质重塑活性，并证明端粒保护蛋白介导的端粒染色质压缩为染色体末端提供了强大的保护，使其免受DDR机制的影响。
