期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-10179-z
关键词
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资金
- Swiss National Science Foundation [P1EZP3-168771, 31003A_160338]
- European Molecular Biology Organization [IG3576]
- Fundacao para a Ciencia e a Tecnologia [IF/01269/2015, PTDC/MED-ONC/28282/2017, PTDC/BIA-MOL/29352/2017]
- Cancer Council of Victoria
- Australian National Health and Medical Research Council [APP1139099]
- Buxton trust
- Victorian Government's OIS Program
- Fundacao para a Ciencia e a Tecnologia/Ministerio da Ciencia, Tecnologia e Ensino Superior (MCTES) through Fundos do Orcamento de Estado [UID/BIM/50005/2019]
- Swiss National Science Foundation (SNF) [P1EZP3_168771, 31003A_160338] Funding Source: Swiss National Science Foundation (SNF)
- Fundação para a Ciência e a Tecnologia [PTDC/BIA-MOL/29352/2017, PTDC/MED-ONC/28282/2017] Funding Source: FCT
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 ALTassociated 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.
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