Nuclear actin and DNA replication stress regulate telomere maintenance by telomerase

Ashley Harman, Melissa Kartawinata, Nohad M. Maroun, Darren R. Nguyen, Shabita Rahman, William E. Hughes, Kevin Winardi, Scott B. Cohen, Anthony J. Cesare, Noa Lamm and Tracy M. Bryan ()
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Ashley Harman: University of Sydney, Cell Biology Unit, Children’s Medical Research Institute, Faculty of Medicine and Health
Melissa Kartawinata: University of Sydney, Cell Biology Unit, Children’s Medical Research Institute, Faculty of Medicine and Health
Nohad M. Maroun: University of Sydney, Cell Biology Unit, Children’s Medical Research Institute, Faculty of Medicine and Health
Darren R. Nguyen: University of Sydney, Cell Biology Unit, Children’s Medical Research Institute, Faculty of Medicine and Health
Shabita Rahman: University of Sydney, Cell Biology Unit, Children’s Medical Research Institute, Faculty of Medicine and Health
William E. Hughes: University of Sydney, Advanced Imaging Facility, Children’s Medical Research Institute, Faculty of Medicine and Health
Kevin Winardi: University of Sydney, Cell Biology Unit, Children’s Medical Research Institute, Faculty of Medicine and Health
Scott B. Cohen: University of Sydney, Cell Biology Unit, Children’s Medical Research Institute, Faculty of Medicine and Health
Anthony J. Cesare: University of Sydney, Genome Integrity Unit, Children’s Medical Research Institute, Faculty of Medicine and Health
Noa Lamm: University of Sydney, Nuclear Dynamics Group, Children’s Medical Research Institute, Faculty of Medicine and Health
Tracy M. Bryan: University of Sydney, Cell Biology Unit, Children’s Medical Research Institute, Faculty of Medicine and Health

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract The recruitment of telomerase to telomeres is a tightly regulated process which is stimulated by replication stress and the DNA damage response regulatory kinase ATR, via an unknown mechanism. Here, we demonstrate that nuclear filamentous actin is important for the stable interaction of telomerase with telomeres in immortal human cells, resulting in productive telomere elongation by telomerase in an actin-dependent manner. This process is regulated by both ATR and mTOR kinases, and employs other regulators of actin structure and function, such as WASP, ARP2/3 and myosin. Nuclear filamentous actin serves as a site for telomerase recruitment, which is mediated by telomere tethering on actin fibers in response to replication stress, allowing telomerase to localize to telomeres containing stalled replication forks. Overall, these data demonstrate that, in human cells which express telomerase, telomeric replication stress triggers the recruitment of telomerase to telomeres via a nuclear actin network, enabling telomere length maintenance.

Date: 2025
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DOI: 10.1038/s41467-025-66506-0

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