title: HSF4 is involved in DNA damage repair through regulation of Rad51.
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.
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
authors.forename: Xiukun
authors.initials: X
authors.lastname: Cui
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Rong
authors.initials: R
authors.lastname: Du
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Stephen
authors.initials: S
authors.lastname: Archacki
authors.forename: Yuexuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Mingxiong
authors.initials: M
authors.lastname: Yuan
authors.forename: Tie
authors.initials: T
authors.lastname: Ke
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Duanzhuo
authors.initials: D
authors.lastname: Li
authors.forename: Chang
authors.initials: C
authors.lastname: Li
authors.forename: David Wan-Cheng
authors.initials: DW
authors.lastname: Li
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Tang
authors.forename: Zhan
authors.initials: Z
authors.lastname: Yin
authors.forename: Mugen
authors.initials: M
authors.lastname: Liu
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000494:pharmacology; D002386:Cataract / Q000235:genetics*; D002454:Cell Differentiation; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007908:Lens, Crystalline / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D015027:Zebrafish
chemical_list: D004268:DNA-Binding Proteins; C102948:HSF4 protein, human; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D014157:Transcription Factors; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D002166:Camptothecin