MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.
Cell Rep. 2013 Sep 12;4(5):853-60. doi: 10.1016/j.celrep.2013.07.033. Epub 2013 Aug 29.
SLX4, a scaffold for structure-specific DNA repair nucleases, is important for several types of DNA repair. Many repair proteins bind to sites of DNA damage, resulting in subnuclear "foci," but SLX4 forms foci in human cells even without DNA damage. Using several approaches, we show that most, but not all, SLX4 foci localize to telomeres in a range of human cell lines irrespective of the mechanisms used to maintain telomere length. The SLX1 Holliday-junction-processing enzyme is recruited to telomeres by SLX4, and SLX4, in turn, is recruited by a motif that binds to the shelterin subunit TRF2 directly. We also show that TRF2-dependent recruitment of SLX4 prevents telomere damage. Furthermore, SLX4 prevents telomere lengthening and fragility in a manner that appears to be independent of telomere association. These findings reveal that SLX4 plays multiple roles in regulating telomere homeostasis.
SLX4 是一种结构特异性 DNA 修复核酸酶的支架，对多种类型的 DNA 修复很重要。许多修复蛋白结合到 DNA 损伤部位，导致核内“焦点”，但 SLX4 甚至在没有 DNA 损伤的情况下也会在人细胞中形成焦点。通过几种方法，我们发现大多数（但不是全部）SLX4 焦点定位于端粒，无论用于维持端粒长度的机制如何，这在一系列人类细胞系中都是如此。SLX1 霍利迪连接处理酶通过 SLX4 被招募到端粒，而 SLX4 反过来又被一个直接与庇护体亚基 TRF2 结合的基序招募。我们还表明，TRF2 依赖性 SLX4 募集可防止端粒损伤。此外，SLX4 以一种似乎独立于端粒关联的方式防止端粒延长和脆弱。这些发现揭示了 SLX4 在调节端粒动态平衡中发挥多种作用。
