DNA damage induces nuclear actin filament assembly by Formin -2 and Spire-½ that promotes efficient DNA repair. [corrected].
Actin filaments assemble inside the nucleus in response to multiple cellular perturbations, including heat shock, protein misfolding, integrin engagement, and serum stimulation. We find that DNA damage also generates nuclear actin filaments-detectable by phalloidin and live-cell actin probes-with three characteristic morphologies: (i) long, nucleoplasmic filaments; (ii) short, nucleolus-associated filaments; and (iii) dense, nucleoplasmic clusters. This DNA damage-induced nuclear actin assembly requires two biologically and physically linked nucleation factors: Formin-2 and Spire-1/Spire-2. Formin-2 accumulates in the nucleus after DNA damage, and depletion of either Formin-2 or actin's nuclear import factor, importin-9, increases the number of DNA double-strand breaks (DSBs), linking nuclear actin filaments to efficient DSB clearance. Nuclear actin filaments are also required for nuclear oxidation induced by acute genotoxic stress. Our results reveal a previously unknown role for nuclear actin filaments in DNA repair and identify the molecular mechanisms creating these nuclear filaments.
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.
Brittany J
BJ
Belin
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.
Terri
T
Lee
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.
R Dyche
RD
Mullins
D008841:Actin Cytoskeleton / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D000080865:Formins; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D055503:Protein Multimerization
C587953:Fmn2 protein, human; D000080865:Formins; D008840:Microfilament Proteins; D009687:Nuclear Proteins; C000592292:SPIRE1 protein, human; C000608602:SPIRE2 protein, human
DNA damage; cell biology; cytoskeleton; human; nuclear actin; nuclear oxidation