Scholarlink

Background <p>Inflammation and genomic instability are among the hallmarks of human cancer. Proinflammatory cytokines induce DNA damage through the accumulation of reactive oxygen and nitrogen species (RONS), which often leads to base alternations. The link between proinflammatory cytokines and chromosomal instability remains largely elusive.</p> Results <p>Here, we report that the mitotic checkpoint protein p31<sup>comet</sup> (MAD2L1BP) is modified by linear ubiquitination via the E3 ubiquitin ligase HOIP after cytokine stimulation. HOIP-mediated polyubiquitination of p31<sup>comet</sup> occurs on its C-terminal lysine residues. Ubiquitinated p31<sup>comet</sup> displays reduced binding to PLK1, which phosphorylates and inactivates p31<sup>comet</sup>. Thus HOIP positively&#xa0; regulates p31<sup>comet</sup> function. Consistent with this notion, HOIP-deficient cells exhibit prolonged mitotic duration similar to p31<sup>comet</sup> knockout. Mitotic defects are also more prevalent in cells without HOIP or p31<sup>comet</sup>. Moreover, compared with the cells expressing wild-type p31<sup>comet</sup>, cells expressing a ubiquitination-deficient p31<sup>comet</sup> mutant take more time to complete the M phase.</p> Conclusions <p>Our results together uncover a mechanistic link between the proinflammatory cytokines and the mitotic checkpoint pathways. This molecular switch could be explored as a potential therapeutic target in inflammation-driving or p31<sup>comet</sup> overexpressed cancer types.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Linear ubiquitination of p31comet by HOIP couples cytokine response with mitotic regulation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年6月3日

查看全文
  • Yifeng Gao,
  • Qing Yin,
  • Yaser Gamallat,
  • Michael G. Grant,
  • Aidan H. Snell,
  • Xingxing Shi,
  • Lara N. Ulstad,
  • Arshita Singh,
  • Tingan Chen,
  • Joseph O. Johnson,
  • Dorina Avram,
  • Lixin Wan

摘要

Background

Inflammation and genomic instability are among the hallmarks of human cancer. Proinflammatory cytokines induce DNA damage through the accumulation of reactive oxygen and nitrogen species (RONS), which often leads to base alternations. The link between proinflammatory cytokines and chromosomal instability remains largely elusive.

Results

Here, we report that the mitotic checkpoint protein p31comet (MAD2L1BP) is modified by linear ubiquitination via the E3 ubiquitin ligase HOIP after cytokine stimulation. HOIP-mediated polyubiquitination of p31comet occurs on its C-terminal lysine residues. Ubiquitinated p31comet displays reduced binding to PLK1, which phosphorylates and inactivates p31comet. Thus HOIP positively  regulates p31comet function. Consistent with this notion, HOIP-deficient cells exhibit prolonged mitotic duration similar to p31comet knockout. Mitotic defects are also more prevalent in cells without HOIP or p31comet. Moreover, compared with the cells expressing wild-type p31comet, cells expressing a ubiquitination-deficient p31comet mutant take more time to complete the M phase.

Conclusions

Our results together uncover a mechanistic link between the proinflammatory cytokines and the mitotic checkpoint pathways. This molecular switch could be explored as a potential therapeutic target in inflammation-driving or p31comet overexpressed cancer types.