Nuclear Myosin VI stabilises Ku-associated DNA ends during non-homologous end joining
- 1University of Sheffield
Abstract
DNA double-strand breaks (DSBs) require rapid signalling and physical stabilisation of broken DNA ends to preserve genome integrity. Here, we identify myosin VI (MVI) as an ATM-regulated component of the DSB response. DNA damage induces rapid nuclear accumulation and nanoscale reorganisation of MVI across multiple cell models, in an ATM-dependent manner. Pharmacological or genetic perturbation of MVI attenuates {gamma}H2AX signalling and disrupts Ku80 organisation, while DNA damage persists. This leads to increased sensitivity to cisplatin and bleomycin. Super-resolution imaging reveals spatial association of MVI with Ku80-containing repair structures, implicating MVI in non-homologous end joining (NHEJ). In a minimal reconstituted system, MVI and actin enhance the proximity of Ku70/80-bound DNA ends. Together, our findings identify MVI as a regulator of DSB repair that links ATM signalling to Ku-associated DNA-end stabilisation and suggest that targeting MVI may sensitise tumour cells to genotoxic therapy.
Related
- Alternative Splicing of Homologous Recombination Genes Is Associated with Homologous Recombination Deficiency and Immunoregulatory Phenotypes in Breast Cancer
- Promoter CpG island hypomethylation and overexpression of molecules homologous to the muscle autoantigens acetylcholine receptor and ryanodine receptor in thymoma epithelial cells associated with myasthenia gravis.
- USP25 stabilises GLI1 through K48‐linked deubiquitination within a reciprocal regulatory circuit in osteoarthritis models
- Tamarixetin promotes ferroptosis-associated redox stress and compensatory activation of nuclear factor erythroid 2-related factor 2 in hepatoma cells
- Electroacupuncture regulates lipid metabolism through PPARγ-associated LXRα signaling: from nuclear receptor signaling to cardiovascular protection
BibTeX
@misc{alanazi2026nuclear,
title = {{Nuclear Myosin VI stabilises Ku-associated DNA ends during non-homologous end joining}},
author = {A. Alanazi and A. Cook and I. Shahid-Fuente and N. Fili and T. Venit and A.-M. Gherghelas and N. B. Hitchcock and A. Moreno Mitchell and J. Arron and T. L. Chew and L. Wang and P. Percipalle and C. P. Toseland},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.01.748478},
url = {https://www.biorxiv.org/content/10.64898/2026.09.01.748478v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Nuclear Myosin VI stabilises Ku-associated DNA ends during non-homologous end joining
AU - A. Alanazi
AU - A. Cook
AU - I. Shahid-Fuente
AU - N. Fili
AU - T. Venit
AU - A.-M. Gherghelas
AU - N. B. Hitchcock
AU - A. Moreno Mitchell
AU - J. Arron
AU - T. L. Chew
AU - L. Wang
AU - P. Percipalle
AU - C. P. Toseland
PY - 2026
DA - 2026/09/01
PB - bioRxiv
DO - 10.64898/2026.09.01.748478
UR - https://www.biorxiv.org/content/10.64898/2026.09.01.748478v1
AB - DNA double-strand breaks (DSBs) require rapid signalling and physical stabilisation of broken DNA ends to preserve genome integrity. Here, we identify myosin VI (MVI) as an ATM-regulated component of the DSB response. DNA damage induces rapid nuclear accumulation and nanoscale reorganisation of MVI across multiple cell models, in an ATM-dependent manner. Pharmacological or genetic perturbation of MVI attenuates {gamma}H2AX signalling and disrupts Ku80 organisation, while DNA damage persists. This leads to increased sensitivity to cisplatin and bleomycin. Super-resolution imaging reveals spatial association of MVI with Ku80-containing repair structures, implicating MVI in non-homologous end joining (NHEJ). In a minimal reconstituted system, MVI and actin enhance the proximity of Ku70/80-bound DNA ends. Together, our findings identify MVI as a regulator of DSB repair that links ATM signalling to Ku-associated DNA-end stabilisation and suggest that targeting MVI may sensitise tumour cells to genotoxic therapy.
ER -