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

Author

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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
    University of Melbourne)

  • Claus M. Azzalin

    (Faculdade de Medicina da Universidade de Lisboa)

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.

Suggested Citation

  • Bruno Silva & Richard Pentz & Ana Margarida Figueira & Rajika Arora & Yong Woo Lee & Charlotte Hodson & Harry Wischnewski & Andrew J. Deans & Claus M. Azzalin, 2019. "FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10179-z
    DOI: 10.1038/s41467-019-10179-z
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    Cited by:

    1. Sile F. Yang & Christopher B. Nelson & Jadon K. Wells & Madushan Fernando & Robert Lu & Joshua A. M. Allen & Lisa Malloy & Noa Lamm & Vincent J. Murphy & Joel P. Mackay & Andrew J. Deans & Anthony J. , 2024. "ZNF827 is a single-stranded DNA binding protein that regulates the ATR-CHK1 DNA damage response pathway," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Chia-Yu Guh & Hong-Jhih Shen & Liv WeiChien Chen & Pei-Chen Chiu & I-Hsin Liao & Chen-Chia Lo & Yunfei Chen & Yu-Hung Hsieh & Ting-Chia Chang & Chien-Ping Yen & Yi-Yun Chen & Tom Wei-Wu Chen & Liuh-Yo, 2022. "XPF activates break-induced telomere synthesis," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Frances Karla Kusuma & Aishvaryaa Prabhu & Galen Tieo & Syed Moiz Ahmed & Pushkar Dakle & Wai Khang Yong & Elina Pathak & Vikas Madan & Yan Yi Jiang & Wai Leong Tam & Dennis Kappei & Peter Dröge & H. , 2023. "Signalling inhibition by ponatinib disrupts productive alternative lengthening of telomeres (ALT)," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. Ilaria Rosso & Corey Jones-Weinert & Francesca Rossiello & Matteo Cabrini & Silvia Brambillasca & Leonel Munoz-Sagredo & Zeno Lavagnino & Emanuele Martini & Enzo Tedone & Massimiliano Garre’ & Julio A, 2023. "Alternative lengthening of telomeres (ALT) cells viability is dependent on C-rich telomeric RNAs," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    5. S. Cohen & A. Guenolé & I. Lazar & A. Marnef & T. Clouaire & D. V. Vernekar & N. Puget & V. Rocher & C. Arnould & M. Aguirrebengoa & M. Genais & N. Firmin & R. A. Shamanna & R. Mourad & V. A. Bohr & V, 2022. "A POLD3/BLM dependent pathway handles DSBs in transcribed chromatin upon excessive RNA:DNA hybrid accumulation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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