title: p53 suppresses hyper-recombination by modulating BRCA1 function.
abstract: Both p53 and BRCA1 are tumor suppressors and are involved in a number of cellular processes including cell cycle arrest, apoptosis, transcriptional regulation, and DNA damage repair. Some studies have suggested that the association of BRCA1 and p53 is required for transcriptional regulation of genes involved in cell replication and DNA repair pathways. However, the relationship between the two proteins in molecular mechanisms of DNA repair is still not clear. Therefore, we sought to determine whether there is a functional link between p53 and BRCA1 in DNA repair. Firstly, using a plasmid recombination substrate, pDR-GFP, integrated into the genome of breast cancer cell line MCF7, we have demonstrated that p53 suppressed Rad51-mediated hyper-recombinational repair by two independent cell models of HPV-E6 induced p53 inactivation and p53 knockdown assay. Our study further indicated that p53 mediated homologous recombination (HR) through inhibiting BRCA1 over-function via mechanism of transcription regulation in response to DNA repair. Since it was found p53 and BRCA1 existed in a protein complex, indicating both proteins may be associated at post-transcriptional level. Moreover, defective p53-induced hyper-recombination was associated with cell radioresistance and chromosomal stability, strongly supporting the involvement of p53 in the inhibition of hyper-recombination, which led to genetic stability and cellular function in response to DNA damage. In addition, it was found that p53 loss rescued BRCA1 deficiency via recovering HR and chromosomal stability, suggesting that p53 is also involved in the HR-inhibition independently of BRCA1. Thus, our data indicated that p53 was involved in inhibiting recombination by both BRCA1-dependent and -independent mechanisms, and there is a functional link between p53-suppression and BRCA1-promotion in regulation of HR activity at transcription level and possible post-transcription level.
authors.affiliation: Department of Environment and Health, School of public health, Shandong University, Jinan, Shandong Province 250012, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Dong
authors.affiliation: Department of Environment and Health, School of public health, Shandong University, Jinan, Shandong Province 250012, China.
authors.forename: Fengmei
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Environment and Health, School of public health, Shandong University, Jinan, Shandong Province 250012, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Environment and Health, School of public health, Shandong University, Jinan, Shandong Province 250012, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Environment and Health, School of public health, Shandong University, Jinan, Shandong Province 250012, China.
authors.forename: Xipeng
authors.initials: X
authors.lastname: Zhao
authors.affiliation: The Second Hospital of Shandong University, Jinan, Shandong Province 250033, China.
authors.forename: Gongshe
authors.initials: G
authors.lastname: Guo
authors.affiliation: Department of Radiation Oncology and Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States.
authors.forename: Simon N
authors.initials: SN
authors.lastname: Powell
authors.affiliation: Department of Environment and Health, School of public health, Shandong University, Jinan, Shandong Province 250012, China. Electronic address: fengzhihui@sdu.edu.cn.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Feng
mesh_terms: D019313:BRCA1 Protein / Q000378:metabolism*; D045744:Cell Line, Tumor; D043171:Chromosomal Instability / Q000528:radiation effects; D004249:DNA Damage; D006801:Humans; D051135:Rad51 Recombinase / Q000378:metabolism; D011839:Radiation, Ionizing; D011995:Recombination, Genetic / Q000235:genetics* / Q000528:radiation effects; D014158:Transcription, Genetic / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; D016159:Tumor Suppressor Protein p53; D051135:Rad51 Recombinase
keywords: BRCA1; Chromosomal stability; Homologous recombination; Hyper-recombination; p53