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

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

Wednesday, 24.07.2019

Authors and affiliations:

Bruno Silva(1), Richard Pentz(1), Ana Margarida Figueira(1), Rajika Arora(1), Yong Woo Lee(1), Charlotte Hodson(2), Harry Wischnewski(3), Andrew J. Deans(2,4), and Claus M. Azzalin(1)

(1)Instituto de Medicina Molecular João Lobo Antunes (iMM), Faculdade de Medicina da Universidade de Lisboa, Lisbon, 1649-028, Portugal

(2)Genome Stability Unit, St. Vincent’s Institute of Medical Research, Fitzroy, 3065, VIC, Australia

(3)Institute of Biochemistry (IBC), Eidgenössische Technische Hochschule Zürich (ETHZ), Zürich, 8093, Switzerland

(4)Department of Medicine (St Vincent’s Hospital), University of Melbourne, Fitzroy, 3065, VIC, Australia


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.

Nature Communications

https://www.nature.com/articles/s41467-019-10179-z