PUBLICATION
CITK modulates BRCA1 recruitment at DNA double strand breaks sites through HDAC6
- Authors
- Iegiani, G., Pallavicini, G., Pezzotta, A., Brix, A., Ferraro, A., Gai, M., Boda, E., Bielas, S.L., Pistocchi, A., Di Cunto, F.
- ID
- ZDB-PUB-250421-6
- Date
- 2025
- Source
- Cell Death & Disease 16: 320320 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Zebrafish/genetics
- Animals
- BRCA1 Protein*/genetics
- BRCA1 Protein*/metabolism
- Humans
- Intracellular Signaling Peptides and Proteins*/genetics
- Intracellular Signaling Peptides and Proteins*/metabolism
- Histone Deacetylase 6*/genetics
- Histone Deacetylase 6*/metabolism
- Microtubules/metabolism
- DNA Repair
- Protein Serine-Threonine Kinases*/genetics
- Protein Serine-Threonine Kinases*/metabolism
- DNA Breaks, Double-Stranded*
- PubMed
- 40254670 Full text @ Cell Death Dis.
Citation
Iegiani, G., Pallavicini, G., Pezzotta, A., Brix, A., Ferraro, A., Gai, M., Boda, E., Bielas, S.L., Pistocchi, A., Di Cunto, F. (2025) CITK modulates BRCA1 recruitment at DNA double strand breaks sites through HDAC6. Cell Death & Disease. 16:320320.
Abstract
Citron Kinase (CITK) is a protein encoded by the CIT gene, whose pathogenic variants underlie microcephalic phenotypes that characterize MCPH17 syndrome. In neural progenitors, CITK loss leads to microtubule instability, resulting in mitotic spindle positioning defects, cytokinesis failure, and accumulation of DNA double strand breaks (DSBs), ultimately resulting in TP53-dependent senescence and apoptosis. Although DNA damage accumulation has been associated with impaired homologous recombination (HR), the role of CITK in this process and whether microtubule dynamics are involved is still unknown. In this report we show that CITK is required for proper BRCA1 localization at sites of DNA DSBs. We found that CITK's scaffolding, rather than its catalytic activity, is necessary for maintaining BRCA1 interphase levels in progenitor cells during neurodevelopment. CITK regulates the nuclear levels of HDAC6, a modulator of both microtubule stability and DNA damage repair. Targeting HDAC6 in CITK-deficient cells increases microtubule stability and recovers BRCA1 localization defects and DNA damage levels to that detected in controls. In addition, the CIT-HDAC6 axis is functionally relevant in a MCPH17 zebrafish model, as HDAC6 targeting recovers the head size phenotype produced by interfering with the CIT orthologue gene. These data provide novel insights into the functional interplay between HR and microtubule dynamics and into the pathogenesis of CITK based MCPH17, which may be relevant for development of therapeutic strategies.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping