The FANCM-BLM-TOP3A-RMI Complex Suppresses Alternative Lengthening of Telomeres (ALT)

Overview

Journal Nat Commun

Specialty Biology

Date 2019 May 30

PMID 31138797

Citations 92

Authors

Robert Lu

Julienne J ORourke

Alexander P Sobinoff

Joshua A M Allen

Christopher B Nelson

Christopher G Tomlinson

Michael Lee

Roger R Reddel

Andrew J Deans

Hilda A Pickett

Affiliations

Soon will be listed here.

Abstract

The collapse of stalled replication forks is a major driver of genomic instability. Several committed mechanisms exist to resolve replication stress. These pathways are particularly pertinent at telomeres. Cancer cells that use Alternative Lengthening of Telomeres (ALT) display heightened levels of telomere-specific replication stress, and co-opt stalled replication forks as substrates for break-induced telomere synthesis. FANCM is a DNA translocase that can form independent functional interactions with the BLM-TOP3A-RMI (BTR) complex and the Fanconi anemia (FA) core complex. Here, we demonstrate that FANCM depletion provokes ALT activity, evident by increased break-induced telomere synthesis, and the induction of ALT biomarkers. FANCM-mediated attenuation of ALT requires its inherent DNA translocase activity and interaction with the BTR complex, but does not require the FA core complex, indicative of FANCM functioning to restrain excessive ALT activity by ameliorating replication stress at telomeres. Synthetic inhibition of FANCM-BTR complex formation is selectively toxic to ALT cancer cells.

Citing Articles

Multiple functions of the ALT favorite helicase, BLM.

Chang S, Tan J, Bao R, Zhang Y, Tong J, Jia T Cell Biosci. 2025; 15(1):31.

PMID: 40025590 PMC: 11871798. DOI: 10.1186/s13578-025-01372-3.

Editorial: Exploring genomic instability of cancers: applications in diagnosis and treatment.

Zhang D, Lin S, Lee M Front Cell Dev Biol. 2025; 13:1528281.

PMID: 39989984 PMC: 11842372. DOI: 10.3389/fcell.2025.1528281.

Locking the gates of immortality: targeting alternative lengthening of telomeres (ALT) pathways.

Mishra A, Patel T Med Oncol. 2025; 42(3):78.

PMID: 39964637 DOI: 10.1007/s12032-025-02627-2.

Elevated reactive oxygen species can drive the alternative lengthening of telomeres pathway in ATRX-null cancers.

Goncalves T, Cunniffe S, Ma T, Mattis N, Rose A, Kent T Nucleic Acids Res. 2025; 53(4).

PMID: 39921567 PMC: 11806356. DOI: 10.1093/nar/gkaf061.

The BLM-TOP3A-RMI1-RMI2 proximity map reveals that RAD54L2 suppresses sister chromatid exchanges.

Ho J, Cheng E, Wong C, St-Germain J, Dunham W, Raught B EMBO Rep. 2025; 26(5):1290-1314.

PMID: 39870965 PMC: 11894219. DOI: 10.1038/s44319-025-00374-z.

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