HSF4 is involved in DNA damage repair through regulation of Rad51

Cui, X., Zhang, J., Du, R., Wang, L., Archacki, S., Zhang, Y., Yuan, M., Ke, T., Li, H., Li, D., Li, C., Li, D.W., Tang, Z., Yin, Z., and Liu, M.
Biochimica et biophysica acta. Molecular basis of disease   1822(8): 1308-1315 (Journal)
Registered Authors
Liu, Mugen, Yin, Zhan
cataract, HSF4, DNA damage, Rad51, camptothecin
MeSH Terms
  • Animals
  • Camptothecin/pharmacology
  • Cataract/genetics*
  • Cell Differentiation
  • Cell Line
  • DNA Damage*
  • DNA Repair*
  • DNA-Binding Proteins/genetics
  • DNA-Binding Proteins/metabolism*
  • Gene Knockdown Techniques
  • Heat-Shock Proteins/genetics*
  • Heat-Shock Proteins/metabolism
  • Humans
  • Lens, Crystalline/metabolism*
  • Promoter Regions, Genetic
  • Rad51 Recombinase/genetics
  • Rad51 Recombinase/metabolism*
  • Transcription Factors/genetics
  • Transcription Factors/metabolism*
  • Transcription, Genetic/drug effects
  • Transfection
  • Zebrafish
22587838 Full text @ BBA Molecular Basis of Disease

Heat shock factor protein 4 (HSF4) is expressed exclusively in the ocular lens and plays a critical role in the lens formation and differentiation. Mutations in the HSF4 gene lead to congenital and senile cataract. However, the molecular mechanisms causing this disease have not been well characterized. DNA damage in lens is a crucial risk factor in senile cataract formation, and its timely repair is essential for maintaining the lens’ transparency. Our study firstly found evidence that HSF4 contributes to the repair of DNA strand breaks. Yet, this does not occur with cataract causative mutations in HSF4. We verify that DNA damage repair is mediated by the binding of HSF4 to a heat shock element in the Rad51 promoter, a gene which assists in the homologous recombination (HR) repair of DNA strand breaks. HSF4 up-regulates Rad51 expression while mutations in HSF4 fail, and DNA does not get repaired. Camptothecin, which interrupts the regulation of Rad51 by HSF4, also affects DNA damage repair. Additionally, with HSF4 knockdown in the lens of Zebrafish, DNA damage was observed and the protein level of Rad51 was significantly lower. Our study presents the first evidence demonstrating that HSF4 plays a role in DNA damage repair and may contribute a better understanding of congenital cataract formation.

Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes