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CITK modulates BRCA1 recruitment at DNA double strand breaks sites through HDAC6

Giorgia Iegiani1,2, Gianmarco Pallavicini1,2, Alex Pezzotta3

  • 1Neuroscience Institute Cavalieri Ottolenghi, Turin, Italy.

Cell Death & Disease
|April 20, 2025
PubMed

Insights

Citron Kinase (CITK) is crucial for DNA repair by ensuring BRCA1 localization. Targeting HDAC6 in CITK-deficient cells restores DNA repair and corrects developmental defects in a zebrafish model.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Neuroscience

Background:

  • Pathogenic variants in the Citron Kinase (CITK) gene cause MCPH17 syndrome, characterized by microcephaly.
  • CITK deficiency in neural progenitors leads to microtubule instability, DNA damage, and cell death.
  • The role of CITK in homologous recombination (HR) and the involvement of microtubule dynamics in DNA repair remain unclear.

Purpose of the Study:

  • To investigate the role of Citron Kinase (CITK) in DNA double-strand break (DSB) repair and its connection to microtubule dynamics.
  • To elucidate the mechanism by which CITK influences BRCA1 localization and DNA repair pathways.
  • To explore therapeutic strategies targeting the CITK-HDAC6 axis for MCPH17 syndrome.

Main Methods:

  • Assessed BRCA1 localization at DNA DSB sites in CITK-deficient cells.
  • Investigated the scaffolding versus catalytic activity of CITK in maintaining BRCA1 levels.
  • Examined the regulation of HDAC6 by CITK and its impact on microtubule stability and DNA repair.
  • Utilized a zebrafish model of MCPH17 syndrome to test the efficacy of HDAC6 targeting.

Main Results:

  • CITK is essential for proper BRCA1 localization to DNA DSBs, independent of its catalytic activity.
  • CITK regulates nuclear HDAC6 levels, impacting both microtubule stability and DNA repair.
  • Targeting HDAC6 in CITK-deficient cells restored BRCA1 localization, reduced DNA damage, and improved microtubule stability.
  • HDAC6 inhibition ameliorated the microcephaly phenotype in a CITK-orthologue zebrafish model.

Conclusions:

  • CITK functions as a scaffold to facilitate BRCA1 recruitment to DNA damage sites, linking microtubule dynamics to homologous recombination repair.
  • The CITK-HDAC6 axis is a key regulator of neurodevelopment and DNA repair, offering a potential therapeutic target for MCPH17 syndrome.

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