ITCH nuclear translocation and H1.2 polyubiquitination negatively regulate the DNA damage response

Lufen Chang, Lei Shen, Hu Zhou, Jing Gao, Hangyi Pan, Li Zheng, Brian Armstrong, Yang Peng, Guang Peng, Binhua P. Zhou, Steven T. Rosen, Binghui Shen

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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 axismay confer TNBC cells with a DDR repression to counteract the replication stress and increase cancer cell survivorship and growth potential.

Original languageEnglish
Pages (from-to)824-842
Number of pages19
JournalNucleic Acids Research
Issue number2
StatePublished - Jan 25 2019

Bibliographical note

Publisher Copyright:
© 2018 The Author(s).

ASJC Scopus subject areas

  • Genetics


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