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The transcription factor GATA3 is required for homologous recombination repair by regulating CtIP expression

Oncogene volume 36, pages 5168–5176 (2017)Cite this article

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Abstract

GATA3, a critical transcription factor involved in the development of the mammary gland, also plays important roles in mammary tumorigenesis by regulating transcription in coordination with two essential DNA repair factors, PARP1 and BRCA1. However, whether and how GATA3 participates in the process of DNA repair, which is often associated with tumorigenesis, has not been investigated. Here we demonstrate that GATA3 is required for the repair of DNA double-strand breaks (DSBs) by homologous recominbation (HR). Mechanistic studies indicate that at both the protein and the mRNA level, depleting GATA3 leads to reduced expression of CtIP, an essential HR factor involved in end resection, thereby suppressing the repair of DSBs by HR and sensitizing cells to etoposide induced DNA DSBs. Further studies indicate that upon the occurrence of DNA DSBs GATA3 directly binds to the CtIP promoter at the region of −2119 to −2130 and −2274 to −2285, and promotes the transcription of CtIP. Overexpression of CtIP in GATA3 depleted cells rescues the decline of HR, and cell survival in the presence of etoposide. In addition, through data mining analysis, we observed an extremely strong correlation between the expression levels of GATA3 and CtIP in paratumors, but the correlation turned insignificant in mammary tumors. Using vectors encoding GATA3 with mutations frequently occurring in mammary tumors, we found that several mutations on GATA3 led to a dysregulation of CtIP, and therefore HR repair. In summary, our data delineates the regulatory mechanisms of GATA3 in DNA DSB repair and strongly suggests that it might act as a tumor suppressor by promoting CtIP expression and HR to stabilize genomes.

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Acknowledgements

We thank Dr Michael Van Meter for critically reading the manuscript. We thank Yang Yu for helping with the clonogenic assay. We thank Lu Chen for helping create the vector encoding GATA3. We thank TCGA for providing high quality high-throughput data for public analysis. The work was supported by grants from Chinese National Program on Key Basic Research Project (Grant No. 2013CB967600, 2015CB964800), the National Science Foundation of China (Grant No. 81502385, 81622019, 31371396, 31570813, 81402543, 81601212), the 1000 Youth Talents Program, Shanghai Municipal Natural Science Foundation (Grant No. 15ZR1442600), and the Fundamental Research Funds for the Central Universities.

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Authors and Affiliations

  1. Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China

    F Zhang, H Tang, Y Jiang & Z Mao

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  1. F Zhang
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  2. H Tang
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Correspondence to Y Jiang or Z Mao.

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Zhang, F., Tang, H., Jiang, Y. et al. The transcription factor GATA3 is required for homologous recombination repair by regulating CtIP expression. Oncogene 36, 5168–5176 (2017). https://doi.org/10.1038/onc.2017.127

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