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FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops.

Bruno Silva | Richard Pentz | Ana Margarida Figueira | Rajika Arora | Yong Woo Lee | Charlotte Hodson | Harry Wischnewski | Andrew J Deans | Claus M Azzalin
Nature communications | 2019

Telomerase negative immortal cancer cells elongate telomeres through the Alternative Lengthening of Telomeres (ALT) pathway. While sustained telomeric replicative stress is required to maintain ALT, it might also lead to cell death when excessive. Here, we show that the ATPase/translocase activity of FANCM keeps telomeric replicative stress in check specifically in ALT cells. When FANCM is depleted in ALT cells, telomeres become dysfunctional, and cells stop proliferating and die. FANCM depletion also increases ALT-associated marks and de novo synthesis of telomeric DNA. Depletion of the BLM helicase reduces the telomeric replication stress and cell proliferation defects induced by FANCM inactivation. Finally, FANCM unwinds telomeric R-loops in vitro and suppresses their accumulation in cells. Overexpression of RNaseH1 completely abolishes the replication stress remaining in cells codepleted for FANCM and BLM. Thus, FANCM allows controlled ALT activity and ALT cell proliferation by limiting the toxicity of uncontrolled BLM and telomeric R-loops.

Pubmed ID: 31138795

Associated grants

  • Agency: Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation), International
    Id: 31003A_160338
  • Agency: European Molecular Biology Organization (EMBO), International
    Id: IG3576
  • Agency: Cancer Council Victoria, International
    Id: APP1139099

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.

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