BLM and SLX4 play opposing roles in recombination-dependent replication at human telomeres

Alternative lengthening of telomeres (ALT) is a telomere lengthening pathway that predominates in aggressive tumors of mesenchymal origin; however, the underlying mechanism of telomere synthesis is not fully understood. Here, we show that the BLM–TOP3A–RMI (BTR) dissolvase complex is required for ALT-mediated telomere synthesis. We propose that recombination intermediates formed during strand invasion are processed by the BTR complex, initiating rapid and extensive POLD3-dependent telomere synthesis followed by dissolution, with no overall exchange of telomeric DNA. This process is counteracted by the SLX4–SLX1–ERCC4 complex, which promotes resolution of the recombination intermediate, resulting in telomere exchange in the absence of telomere extension. Our data are consistent with ALT being a conservative DNA replication process, analogous to break-induced replication, which is dependent on BTR and counteracted by SLX4 complex-mediated resolution events.

Source: EMBO Journal - October 2, 2017 Category: Molecular Biology Authors: Sobinoff, A. P., Allen, J. A., Neumann, A. A., Yang, S. F., Walsh, M. E., Henson, J. D., Reddel, R. R., Pickett, H. A. Tags: DNA Replication, Repair & Recombination Articles Source Type: research