ITCH nuclear translocation and H1.2 polyubiquitination negatively regulate the DNA damage response. Issue 2 (4th December 2018)

• Record Type: Journal Article
• Authors: Chang, Lufen; Shen, Lei; Zhou, Hu; Gao, Jing; Pan, Hangyi; Zheng, Li; Armstrong, Brian; Peng, Yang; Peng, Guang; Zhou, Binhua P; Rosen, Steven T; Shen, Binghui
• Is Part Of: Nucleic acids research. Volume 47:Issue 2(2019)
• Page Start: 824
• Page End: 842
• Publication Date: 2018-12-04
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gky1199
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: The downregulation of the DNA damage response (DDR) enables aggressive tumors to achieve uncontrolled proliferation against replication stress, but the mechanisms underlying this process in tumors are relatively complex. Here, we demonstrate a mechanism through which a distinct E3 ubiquitin ligase, ITCH, modulates DDR machinery in triple-negative breast cancer (TNBC). We found that expression of a nuclear form of ITCH was significantly increased in human TNBC cell lines and tumor specimens. Phosphorylation of ITCH at Ser257 by AKT led to the nuclear localization of ITCH and ubiquitination of H1.2. The ITCH-mediated polyubiquitination of H1.2 suppressed RNF8/RNF168-dependent formation of 53BP1 foci, which plays important roles in DDR. Consistent with these findings, impaired ITCH nuclear translocation and H1.2 polyubiquitination sensitized cells to replication stress and limited cell growth and migration. AKT activation of ITCH-H1.2 axis may confer TNBC cells with a DDR repression to counteract the replication stress and increase cancer cell survivorship and growth potential.