Citron Kinase Guides BRCA1 to DNA Breaks Using HDAC6

Jim Crocker
23rd April, 2025

Citron Kinase Guides BRCA1 to DNA Breaks Using HDAC6

The loss of Citron Kinase (CITK) in human medulloblastoma cells impairs the recruitment of the DNA repair protein BRCA1 to sites of DNA double-strand breaks (d, l, e-g, m-o), resulting in an accumulation of DNA damage (c, k).

Image adapted from: Iegiani et al. / CC BY (Source)

Key Findings

  • *Neuroscience Institute in Turin* found that Citron Kinase (CITK) protects the DNA of early brain cells
  • Without CITK, DNA damage rises, causing cell death and leading to smaller brain size (microcephaly)
  • Targeting the protein HDAC6 can reverse these effects, suggesting new treatment possibilities
Maintaining the integrity of our genetic material is essential for the proper development and function of the nervous system. Scientists at the Neuroscience Institute in Turin have uncovered new insights into how disruptions in this delicate balance can lead to developmental disorders. Their recent study highlights the critical role of a protein called Citron Kinase (CITK) in safeguarding the DNA of neural progenitor cells, which are early-stage cells that give rise to neurons. CITK is encoded by the CIT gene, and mutations in this gene are known to cause MCPH17 syndrome, a condition characterized by a significantly smaller brain size (microcephaly)[1]. Neural progenitors undergo rapid cell division and must maintain high levels of genome stability to ensure proper brain development. When CITK is lost or dysfunctional, it leads to instability in microtubules, which are structural components that play a key role in cell division. This instability results in defects in the positioning of the mitotic spindle, a structure that segregates chromosomes during cell division, and failures in cytokinesis, the process where a single cell divides into two daughter cells. One of the most damaging consequences of CITK loss is the accumulation of double-strand breaks (DSBs) in DNA. DSBs are severe forms of genetic damage that, if not properly repaired, can lead to cell death or cancer[2][3]. The Nervous Institute’s study found that in the absence of CITK, there is an increase in DSBs, which triggers a cellular response leading to senescence (a state of permanent cell cycle arrest) and apoptosis (programmed cell death) mediated by the TP53 protein. This accumulation of DNA damage disrupts neural homeostasis and contributes to the microcephalic phenotype observed in MCPH17 syndrome[4]. A key finding of the study is the role of CITK in the homologous recombination (HR) pathway, one of the primary mechanisms cells use to repair DSBs accurately[5]. Specifically, CITK is necessary for the proper localization of BRCA1, a protein essential for HR, at the sites of DNA damage. BRCA1 helps in the accurate repair of DSBs by facilitating the search for a homologous DNA sequence to guide the repair process. The researchers discovered that CITK does not rely on its enzymatic activity for this function but rather acts as a scaffolding protein that maintains BRCA1 levels in the nucleus during the critical stages of neurodevelopment. Furthermore, CITK influences the levels of HDAC6 in the nucleus. HDAC6 is a protein that modulates both microtubule stability and DNA damage repair, linking the structural integrity of the cell to its genetic maintenance systems. In CITK-deficient cells, targeting HDAC6 was shown to restore microtubule stability and correct defects in BRCA1 localization and DNA damage levels. This suggests that the CIT-HDAC6 axis is crucial for coordinating the repair of DNA damage with the maintenance of the cellular architecture. The study also utilized a zebrafish model to demonstrate the functional relevance of the CIT-HDAC6 interaction. By targeting HDAC6 in zebrafish with disrupted CIT orthologue genes, researchers were able to recover the head size phenotype, providing a promising avenue for potential therapeutic strategies. This animal model underscores the importance of HDAC6 in mediating the effects of CITK loss and highlights the broader implications for understanding and potentially treating MCPH17 syndrome. These findings build on previous research that underscores the importance of genome stability in neural development[4]. By elucidating the specific role of CITK in HR and its interaction with HDAC6, the study provides a clearer picture of how genetic stability is maintained during brain development and how its disruption can lead to severe neurological disorders. Additionally, the research advances our understanding of the mechanisms governing DSB repair pathway choice, a topic extensively reviewed in earlier studies[2][3][5]. The ability of CITK to influence BRCA1 localization and interact with HDAC6 adds a new layer to the complex regulation of DNA repair processes, emphasizing the interconnectedness of cellular structural dynamics and genetic maintenance. Overall, the Neuroscience Institute’s research offers valuable insights into the molecular underpinnings of brain development disorders. By identifying the critical functions of CITK in maintaining genome stability and microtubule dynamics, the study opens up new possibilities for developing targeted therapies to address the genetic and structural defects that contribute to conditions like MCPH17 syndrome. This work not only enhances our fundamental understanding of neural development but also paves the way for future investigations into therapeutic interventions that can mitigate the effects of genetic mutations on brain health.

HealthGeneticsBiochem

References

Main Study

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

Published 20th April, 2025

https://doi.org/10.1038/s41419-025-07655-4

Related Studies

2) Mechanisms and Consequences of Double-Strand DNA Break Formation in Chromatin.

https://doi.org/10.1002/jcp.25048

3) DNA double-strand break repair-pathway choice in somatic mammalian cells.

https://doi.org/10.1038/s41580-019-0152-0

4) Maintaining genome stability in the nervous system.

https://doi.org/10.1038/nn.3537

5) Protein dynamics of human RPA and RAD51 on ssDNA during assembly and disassembly of the RAD51 filament.

https://doi.org/10.1093/nar/gkw1125


Related Articles

An unhandled error has occurred. Reload 🗙