Abstract
HOPS is a ubiquitin-like protein implicated in many aspects of cellular function including the regulation of mitotic activity, proliferation, and cellular stress responses. In this study, we focused on the complex relationship between HOPS and the tumor suppressor p53, investigating both transcriptional and non-transcriptional p53 responses. Here, we demonstrated that Hops heterozygous mice and mouse embryonic fibroblasts exhibit an impaired DNA-damage response to etoposide-induced double-strand breaks when compared to wild-type genes. Specifically, alterations in HOPS levels caused significant defects in the induction of apoptosis, including a reduction in p53 protein level and percentage of apoptotic cells. We also analyzed the effect of reduced HOPS levels on the DNA-damage response by examining the transcript profiles of p53-dependent genes, showing a suggestive deregulation of the mRNA levels for a number of p53-dependent genes. Taken together, these results show an interesting haploinsufficiency effect mediated by Hops monoallelic deletion, which appears to be enough to destabilize the p53 protein and its functions. Finally, these data indicate a novel role for Hops as a tumor-suppressor gene in DNA damage repair in mammalian cells.
Highlights
Hepatocyte Odd Protein Shuttling (HOPS), known as Trans-Membrane and Ubiquitin-like protein-1 (TMUB-1)—hereafter referred to as HOPS—is a ubiquitin-like protein that acts as a modifier in the control of several cell functions such as centrosome assembly, proliferation, inflammation, and apoptosis [1,2,3,4]
We demonstrated that Hops heterozygous mice and mouse embryonic fibroblasts exhibit an impaired DNA-damage response to etoposide-induced double-strand breaks when compared to wild-type genes
We demonstrated that in vitro Hops+/− and Hops−/− mouse embryonic fibroblasts (MEFs) and in vivo responsive organs from corresponding mice exhibited an impaired DNA-damage response to doublestrand breaks (DSBs) induced by etoposide when compared to their wild-type counterparts
Summary
Hepatocyte Odd Protein Shuttling (HOPS), known as Trans-Membrane and Ubiquitin-like protein-1 (TMUB-1)—hereafter referred to as HOPS—is a ubiquitin-like protein that acts as a modifier in the control of several cell functions such as centrosome assembly, proliferation, inflammation, and apoptosis [1,2,3,4]. During liver regeneration, HOPS inhibits STAT3 pathways, negatively controlling hepatocyte proliferation [8]. In controlling p19Arf stabilization, HOPS retains MDM2 (Mouse Double Minute 2)—the main negative p53 regulator—and controls p53 half-life [3]. This complex circuit is essential for maintaining and regulating intracellular levels and p53 activity, since many tumors can arise due to alterations affecting these circuits. HOPS, through its UBL, acts as a modifier to control p53 stability, inhibiting ubiquitination and sustaining the cytoplasmic concentration of p53 to trigger mitochondrial apoptosis. The role of HOPS as a modifier has been demonstrated in controlling the activation of NF-kB pathway, regulating TRAF-6 stability and, in turn, modulating NF-kB response to LPS. Lack of HOPS is associated with a reduction in inflammatory response after treatment [12]
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