DOC45, a novel DNA damage-regulated nucleocytoplasmic ATPase that is overexpressed in multiple human malignancies

Hong Sun1, Xiuquan Luo, JoAnne Montalbano

  • 1Department of Pharmacology, State University of New York, Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.

Insights

We identified a new gene, DNA damage-regulated overexpressed in cancer 45 (DOC45), that is downregulated by DNA damage but overexpressed in many cancers. DOC45 is a novel ATPase involved in cell proliferation and survival.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • The cellular response to DNA damage involves complex regulatory networks.
  • Understanding novel genes involved in stress response and cancer is crucial for therapeutic development.

Purpose of the Study:

  • To characterize a novel gene, DNA damage-regulated overexpressed in cancer 45 (DOC45).
  • To investigate the role of DOC45 in DNA damage response, cancer development, and cellular processes.

Main Methods:

  • Gene expression analysis using DNA damage and endoplasmic reticulum stress agents.
  • Analysis of DOC45 expression in human malignancies.
  • Biochemical assays to determine ATPase activity.
  • Cellular localization studies and nucleocytoplasmic transport inhibition.
  • Gene knockdown experiments using short hairpin RNA (shRNA) in colon cancer cells.

Main Results:

  • DOC45 expression is strongly downregulated by DNA-damaging agents but not ER stress agents.
  • DOC45 is overexpressed in multiple human cancers (colon, rectum, ovary, lung, stomach, uterus).
  • DOC45 possesses nucleotide triphosphate-binding motifs and exhibits ATP hydrolysis activity, functioning as an ATPase.
  • DOC45 shows nucleocytoplasmic distribution and accumulates in nucleoli upon inhibition of nuclear export, suggesting shuttling.
  • DOC45 expression is upregulated during oncogenic Ras transformation and linked to the phosphoinositide 3-kinase pathway.
  • DOC45 knockdown inhibits colon cancer cell proliferation and increases sensitivity to doxorubicin-induced cell death.

Conclusions:

  • DOC45 is a novel ATPase implicated in cellular stress response and tumorigenesis.
  • DOC45 plays a significant role in cell proliferation and survival.
  • DOC45 may serve as a potential tumor marker for various human malignancies.

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