BLM and SLX4 play opposing roles in recombination‐dependent replication at human telomeres |
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| Authors: | Alexander P Sobinoff Joshua AM Allen Axel A Neumann Sile F Yang Monica E Walsh Jeremy D Henson Roger R Reddel Hilda A Pickett |
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| Institution: | 1. Telomere Length Regulation Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW, Australia;2. Cancer Research Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW, Australia;3. Cancer Cell Immortality Group, Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia |
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| Abstract: | 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. |
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| Keywords: |
ALT
BLM
SLX4 telomere recombination telomere synthesis |
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