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Phospho-TRIM21 orchestrates RPA2 ubiquitination switch to promote homologous recombination and tumor

Jie Zhang1,2, Bin Chen3, Feng Xu1,2

  • 1High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Chinese Academy of Sciences, Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, China.

Oncogene
|February 3, 2025
PubMed

Insights

Phosphorylated TRIM21 regulates RPA2 ubiquitination, impacting DNA repair and tumor resistance. This mechanism is crucial for homologous recombination and cancer therapy.

Area of Science:

  • Molecular Biology
  • DNA Repair Mechanisms
  • Cancer Biology

Background:

  • Replication protein A (RPA) complex, particularly RPA2, is vital for DNA repair.
  • Regulation of RPA2-ssDNA interactions and repair protein recruitment post-DNA damage is not fully understood.

Purpose of the Study:

  • To elucidate the novel mechanism of TRIM21 in regulating RPA2 ubiquitination.
  • To understand the role of this regulation in homologous recombination and tumor radio/chemo-resistance.

Main Methods:

  • Investigated TRIM21's role in RPA2 ubiquitination.
  • Analyzed the impact of TRIM21 phosphorylation on RPA2 ubiquitination status.
  • Studied the recruitment of ATRIP/ATR and its relation to RPA2 ubiquitination.
  • Assessed the effect of TRIM21 depletion on cancer cell sensitivity to radio/chemotherapy.

Main Results:

  • TRIM21 mediates K63-linked ubiquitination of RPA2 in undamaged cells.
  • Upon DNA damage, ATR phosphorylates TRIM21, causing a shift to K6-linked ubiquitination of RPA2.
  • This ubiquitination shift stabilizes the RPA2-ATRIP complex, promoting homologous recombination (HR) repair.
  • TRIM21 upregulation in cancers correlates with radio/chemo-resistance; its depletion sensitizes cancer cells.

Conclusions:

  • Phosphorylated TRIM21 is a key regulator of RPA2 ubiquitination in the DNA damage response.
  • This regulatory pathway is critical for homologous recombination repair and tumor resistance to therapy.
  • TRIM21 represents a potential therapeutic target for enhancing cancer treatment efficacy.

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