Mammalian shelterin proteins POT1 and TPP1 form a stable heterodimer that protects chromosome ends and regulates telomerase-mediated telomere extension. However, how POT1 interacts with TPP1 remains unknown. Here we present the crystal structure of the C-terminal portion of human POT1 (POT1C) complexed with the POT1-binding motif of TPP1. The structure shows that POT1C contains two domains, a third OB fold and a Holliday junction resolvase-like domain. Both domains are essential for binding to TPP1. Notably, unlike the heart-shaped structure of ciliated protozoan Oxytricha nova TEBPα–β complex, POT1–TPP1 adopts an elongated V-shaped conformation. In addition, we identify several missense mutations in human cancers that disrupt the POT1C–TPP1 interaction, resulting in POT1 instability. POT1C mutants that bind TPP1 localize to telomeres but fail to repress a DNA damage response and inappropriate repair by A-NHEJ. Our results reveal that POT1 C terminus is essential to prevent initiation of genome instability permissive for tumorigenesis.

The hyper-singular boundary integral equation method of crack analysis in three-dimensional transversely isotropic magnetoelectroelastic media is proposed. Based on the fundamental solutions or Green's functions of three-dimensional transversely isotropic magnetoelectroelastic media and the corresponding Somigliana identity, the boundary integral equations for a planar crack of arbitrary shape in the plane of isotropy are obtained in terms of the extended displacement discontinuities across crack faces. The extended displacement discontinuities include the displacement discontinuities, the electric potential discontinuity and the magnetic potential discontinuity, and correspondingly the extended tractions on crack face represent the conventional tractions, the electric displacement and the magnetic induction boundary values. The near crack tip fields and the intensity factors in terms of the extended displacement discontinuities are derived by boundary integral equation approach. A solution method is proposed by use of the analogy between the boundary integral equations of the magnetoelectroelastic media and the purely elastic materials. The influence of different electric and magnetic boundary conditions, i.e., electrically and magnetically impermeable and permeable conditions, electrically impermeable and magnetically permeable condition, and electrically permeable and magnetically impermeable condition, on the solutions is studied. The crack opening model is proposed to consider the real crack opening and the electric and magnetic fields in the crack cavity under combined mechanical-electric-magnetic loadings. An iteration approach is presented for the solution of the non-linear model. The exact solution is obtained for the case of uniformly applied loadings on the crack faces. Numerical results for a square crack under different electric and magnetic boundary conditions are displayed to demonstrate the proposed method.

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