ARGLU1 enhances promoter-proximal pausing of RNA polymerase II and stimulates DNA damage repair

Nucleic Acids Res. 2024 Jun 10;52(10):5658-5675. doi: 10.1093/nar/gkae208.

Abstract

Arginine and glutamate rich 1 (ARGLU1) is a poorly understood cellular protein with functions in RNA splicing and transcription. Computational prediction suggests that ARGLU1 contains intrinsically disordered regions and lacks any known structural or functional domains. We used adenovirus Early protein 1A (E1A) to probe for critical regulators of important cellular pathways and identified ARGLU1 as a significant player in transcription and the DNA damage response pathway. Transcriptional effects induced by ARGLU1 occur via enhancement of promoter-proximal RNA polymerase II pausing, likely by inhibiting the interaction between JMJD6 and BRD4. When overexpressed, ARGLU1 increases the growth rate of cancer cells, while its knockdown leads to growth arrest. Significantly, overexpression of ARGLU1 increased cancer cell resistance to genotoxic drugs and promoted DNA damage repair. These results identify new roles for ARGLU1 in cancer cell survival and the DNA damage repair pathway, with potential clinical implications for chemotherapy resistance.

MeSH terms

  • Bromodomain Containing Proteins
  • Cell Cycle Proteins* / genetics
  • Cell Cycle Proteins* / metabolism
  • Cell Line, Tumor
  • DNA Damage
  • DNA Repair*
  • DNA-Binding Proteins
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / genetics
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Promoter Regions, Genetic*
  • RNA Polymerase II* / metabolism
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism
  • Transcription, Genetic

Substances

  • BRD4 protein, human
  • Bromodomain Containing Proteins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Jumonji Domain-Containing Histone Demethylases
  • Nuclear Proteins
  • RNA Polymerase II
  • SUB1 protein, human
  • Transcription Factors
  • ARGLU1 protein, human