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 and Claus M. Azzalin ()
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Bruno Silva: Faculdade de Medicina da Universidade de Lisboa
Richard Pentz: Faculdade de Medicina da Universidade de Lisboa
Ana Margarida Figueira: Faculdade de Medicina da Universidade de Lisboa
Rajika Arora: Faculdade de Medicina da Universidade de Lisboa
Yong Woo Lee: Faculdade de Medicina da Universidade de Lisboa
Charlotte Hodson: St. Vincent’s Institute of Medical Research
Harry Wischnewski: Eidgenössische Technische Hochschule Zürich (ETHZ)
Andrew J. Deans: St. Vincent’s Institute of Medical Research
Claus M. Azzalin: Faculdade de Medicina da Universidade de Lisboa

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-10179-z

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