Nuclear insulin-like growth factor 1 receptor phosphorylates proliferating cell nuclear antigen and rescues stalled replication forks after DNA damage
AffiliationUniv Arizona, Phoenix Childrens Hosp, Inst Mol Med
Univ Arizona, Coll Med, Dept Child Hlth
Keywordsinsulin-like growth factor (IGF)
proliferating cell nuclear antigen (PCNA)
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CitationNuclear insulin-like growth factor 1 receptor phosphorylates proliferating cell nuclear antigen and rescues stalled replication forks after DNA damage 2017, 292 (44):18227 Journal of Biological Chemistry
JournalJournal of Biological Chemistry
Rights© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractWe have previously shown that the insulin-like growth factor 1 receptor (IGF-1R) translocates to the cell nucleus, where it binds to enhancer-like regions and increases gene transcription. Further studies have demonstrated that nuclear IGF-1R (nIGF-1R) physically and functionally interacts with some nuclear proteins, i.e. the lymphoid enhancer-binding factor 1 (Lef1), histone H3, and Brahma-related gene-1 proteins. In this study, we identified the proliferating cell nuclear antigen (PCNA) as a nIGF-1R-binding partner. PCNA is a pivotal component of the replication fork machinery and a main regulator of the DNA damage tolerance (DDT) pathway. We found that IGF-1R interacts with and phosphorylates PCNA in human embryonic stem cells and other cell lines. In vitro MS analysis of PCNA co-incubated with the IGF-1R kinase indicated tyrosine residues 60, 133, and 250 in PCNA as IGF-1R targets, and PCNA phosphorylation was followed by mono- and polyubiquitination. Co-immunoprecipitation experiments suggested that these ubiquitination events may be mediated by DDT-dependent E2/E3 ligases (e.g. RAD18 and SHPRH/HLTF). Absence of IGF-1R or mutation of Tyr-60, Tyr-133, or Tyr-250 in PCNA abrogated its ubiquitination. Unlike in cells expressing IGF-1R, externally induced DNA damage in IGF-1R-negative cells caused G(1) cell cycle arrest and S phase fork stalling. Taken together, our results suggest a role of IGF-1R in DDT.
Note12 month embargo; Published online: 18 September 2018
VersionFinal published version
SponsorsSwedish Cancer Foundation; Swedish Research Council; Cancer Society in Stockholm; Swedish Children Cancer Society; Stockholm County Council; Karolinska Institutet