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PBAF loss leads to DNA damage-induced inflammatory signaling through defective G2/M checkpoint maintenance

Hugang Feng1, Karen A Lane1, Theodoros I Roumeliotis1

  • 1The Institute of Cancer Research, London SW3 6JB, United Kingdom.

Genes & Development
|July 28, 2022
PubMed

Insights

Loss of the PBRM1 gene in clear cell renal cancer disrupts the G2/M DNA damage checkpoint. This leads to inflammatory signaling and impacts immunotherapy response in patients with kidney cancer.

Area of Science:

  • Molecular biology
  • Cancer research
  • Immunology

Background:

  • The PBRM1 gene is frequently mutated in clear cell renal cancer (ccRCC).
  • PBRM1 loss is linked to immunotherapy response in kidney cancer, but the underlying mechanisms are not fully understood.
  • DNA damage-induced inflammation influences immunotherapy outcomes.

Purpose of the Study:

  • To elucidate the mechanism by which PBRM1 loss affects DNA damage response and inflammatory signaling in ccRCC.
  • To investigate the role of PBRM1 in maintaining the G2/M checkpoint and its connection to immunotherapy response.

Main Methods:

  • Investigated the impact of PBRM1 deficiency on DNA damage response pathways, including the G2/M checkpoint and p53/p21 signaling.
  • Assessed the role of the DREAM complex in transcriptional repression following DNA damage in PBRM1-deficient cells.
  • Analyzed the activation of cytosolic DNA-sensing pathways and their correlation with PBRM1 status in clinical ccRCC samples.

Main Results:

  • PBRM1 loss delays p53-dependent p21 upregulation after DNA damage, impairing DREAM complex repression.
  • Defective checkpoint control leads to premature mitotic entry with unrepaired DNA, activating inflammatory signaling via cytosolic DNA.
  • PBRM1 mutational status is critical for G2/M checkpoint maintenance, especially given infrequent p53 mutations in renal cancer.
  • PBRM1 deficiency's predictive value for immunotherapy response correlates with cytosolic DNA-sensing pathway activation in patients.

Conclusions:

  • PBRM1 loss compromises the G2/M checkpoint, promoting aberrant cell cycle progression and inflammatory signaling in ccRCC.
  • The findings reveal a novel mechanism linking PBRM1 status, DNA damage response, and immunotherapy efficacy in kidney cancer.
  • PBRM1 mutational status serves as a potential biomarker for predicting therapeutic responses in renal cancer patients.
Keywords:
BAFBAF180DNA damageDREAM complexG2/M checkpointPBRM1SWI/SNFTP53cGASimmunotherapyinflammatory signalingp21

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