A topological mechanism for TRF2-enhanced strand invasion

Telomeres can fold into t-loops that may result from the invasion of the 3' overhang into duplex DNA. Their formation is facilitated in vitro by the telomeric protein TRF2, but very little is known regarding the mechanisms involved. Here we reveal that TRF2 generates positive supercoiling and condenses DNA. Using a variety of TRF2 mutants, we demonstrate a strong correlation between this topological activity and the ability to stimulate strand invasion. We also report that these properties require the combination of the TRF-homology (TRFH) domain of TRF2 with either its N- or C-terminal DNA-binding domains. We propose that TRF2 complexes, by constraining DNA around themselves in a right-handed conformation, can induce untwisting of the neighboring DNA, thereby favoring strand invasion. Implications of this topological model in t-loop formation and telomere homeostasis are discussed.

端粒可折叠成T环，这可能是由于3'突出端侵入双链DNA所致。在体外，端粒蛋白TRF2促进了它们的形成，但对所涉及的机制知之甚少。在此我们揭示，TRF2产生正超螺旋并使DNA凝聚。通过使用多种TRF2突变体，我们证明了这种拓扑活性与刺激链侵入的能力之间存在很强的相关性。我们还报道，这些特性需要TRF2的TRF同源（TRFH）结构域与其N端或C端DNA结合结构域相结合。我们提出，TRF2复合物通过以右手构象将自身周围的DNA约束起来，能够诱导邻近DNA解旋，从而有利于链侵入。讨论了该拓扑模型在T环形成和端粒稳态中的意义。