Abstract PR17: The transcriptional repressor Slug promotes the DNA damage response

Abstract

Abstract The transcriptional repressor Slug/SNAI2 orchestrates epigenetic programs indispensable for tissue self-renewal and tumorigenesis. Although Slug-deficient animals are highly sensitive to lethal irradiation, the direct biological relationship between Slug and the DNA damage response remains largely unexplored. Here we report that Slug interacts with DNA repair proteins, including FANCI, BCCIP and PARP1, in a mass spectrometry screen for Slug binding partners. In response to double-strand breaks (DSBs) induced by irradiation, Slug-deficient cells exhibited a marked delay in the resolution of γH2ax foci. Furthermore, we showed that Slug inhibition significantly impaired DSBs repair that is mediated by homologous recombination. Accordingly, Slug-deficient mouse tissue accumulates DNA damage markers and showed altered nuclear morphology. Mechanistically, Slug interacts with and is stabilized by ATM upon DNA damage. Finally, we demonstrated that Slug depletion sensitizes aggressive triple-negative breast cancer cells to irradiation and chemotherapy. These findings suggest that Slug may be an important regulator of the DNA damage response and an attractive therapeutic target for aggressive cancer types. This abstract is also being presented as Poster B16. Citation Format: Wenhui Zhou, Jian Ouyang, Kathryn Huber, Charlotte Kuperwasser. The transcriptional repressor Slug promotes the DNA damage response [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr PR17.