BLM and SLX4 play opposing roles in break-induced replication at human telomeres — ASN Events
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  3. BLM and SLX4 play opposing roles in break-induced replication at human telomeres

BLM and SLX4 play opposing roles in break-induced replication at human telomeres (#176)

Alexander P Sobinoff 1 , Joshua A.M Allen 1 , Axel A Neumann 2 , Sile F Yang 1 , Monica E Walsh 1 , Jeremy D Henson 3 , Roger R Reddel 2 , Hilda A Pickett 1
  1. Telomere Length Regulation Group, Children’s Medical Research Institute, University of Sydney, Sydney, NSW, Australia
  2. Cancer Research Unit, Children’s Medical Research Institute, Sydney, NSW, Australia
  3. Cancer Cell Immortality Group, Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia

Alternative lengthening of telomeres (ALT) is an homologous recombination (HR)-mediated mechanism for the de novo synthesis of telomeric DNA. Functional understanding of the mechanism has focused on the structural changes that enable ALT telomeres to adopt a recombination permissive state, whilst very little is known about the underlying process of ALT-mediated telomere synthesis. We demonstrate that overexpression of the BLM Holliday junction (HJ) dissolvase promotes both telomeric DNA synthesis and inter-telomeric copying of an integrated telomere tag, but reduces telomere sister chromatid exchange (t-SCE) events specifically in ALT cells. In contrast, overexpression of the SLX4 HJ resolvase inhibits telomere synthesis by ALT, inhibits inter-telomeric copying of the integrated telomere tag, but causes elevated t-SCEs. Simultaneous depletion of both BLM and SLX4 results in the formation of ultrafine telomere bridges detected via CO-FISH in metaphase spreads, suggesting that both proteins are required to process ALT-specific telomeric recombination intermediates, and that in their absence telomere-telomere associations are prolonged. Depletion of one protein affects the telomeric localisation of the other, indicating that BLM and SLX4 compete with one another for telomeric binding. Our results demonstrate that BLM and SLX4 play opposing roles in the processing of telomeric recombination intermediates at ALT telomeres, with BLM promoting telomere synthesis via HJ dissolution and SLX4 inhibiting telomere extension via HJ resolution. Our results contradict the widely accepted view that ALT activity is representative of the frequency of telomere exchange events.

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