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.
Document Type
Article
Publication Date
1-25-2019
Digital Object Identifier (DOI)
https://doi.org/10.1093/nar/gky1199
Funding Information
National Cancer Institute/National Institutes of Health (NCI/NIH) [P30CA033572]; NCI/NIH [R01 CA085344 to B.S.]. Funding for open access charge: NCI/NIH [R01 CA085344].
Related Content
Supplementary Data are available at NAR Online.
Repository Citation
Chang, Lufen; Shen, Lei; Zhou, Hu; Gao, Jing; Pan, Hangyi; Zheng, Li; Armstrong, Brian; Peng, Yang; Peng, Guang; Zhou, Binhua P.; Rosen, Steven T.; and Shen, Binghui, "ITCH Nuclear Translocation and H1.2 Polyubiquitination Negatively Regulate the DNA Damage Response" (2019). Molecular and Cellular Biochemistry Faculty Publications. 161.
https://uknowledge.uky.edu/biochem_facpub/161
Supplementary Data
Included in
Medical Cell Biology Commons, Molecular Biology Commons, Nucleic Acids, Nucleotides, and Nucleosides Commons, Oncology Commons
Notes/Citation Information
Published in Nucleic Acids Research, v. 47, issue 2, p. 824-842.
© The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.