HSF4 is involved in DNA damage repair through regulation of Rad51

Xiukun Cui, Jing Zhang, Rong Du, Lei Wang, Stephen Archacki, Yuexuan Zhang, Mingxiong Yuan, Tie Ke, Hui Li, Duanzhuo Li, Chang Li, David Wan Cheng Li, Zhaohui Tang, Zhan Yin, Mugen Liu

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1308-1315
Number of pages8
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1822
Issue number8
DOIs
StatePublished - Aug 2012
Externally publishedYes

Keywords

  • Camptothecin
  • Cataract
  • DNA damage
  • HSF4
  • Rad51

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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