PBAF loss leads to DNA damage-induced inflammatory signaling through defective G2/M checkpoint maintenance
- Hugang Feng1,
- Karen A. Lane1,
- Theodoros I. Roumeliotis1,
- Penny A. Jeggo2,
- Navita Somaiah1,3,
- Jyoti S. Choudhary1 and
- Jessica A. Downs1
- 1The Institute of Cancer Research, London SW3 6JB, United Kingdom;
- 2Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, United Kingdom;
- 3The Royal Marsden National Health Service Foundation Trust, London SM2 5PT, United Kingdom
- Corresponding author: jessica.downs{at}icr.ac.uk
Abstract
The PBRM1 subunit of the PBAF (SWI/SNF) chromatin remodeling complex is mutated in ∼40% of clear cell renal cancers. PBRM1 loss has been implicated in responses to immunotherapy in renal cancer, but the mechanism is unclear. DNA damage-induced inflammatory signaling is an important factor determining immunotherapy response. This response is kept in check by the G2/M checkpoint, which prevents progression through mitosis with unrepaired damage. We found that in the absence of PBRM1, p53-dependent p21 up-regulation is delayed after DNA damage, leading to defective transcriptional repression by the DREAM complex and premature entry into mitosis. Consequently, DNA damage-induced inflammatory signaling pathways are activated by cytosolic DNA. Notably, p53 is infrequently mutated in renal cancer, so PBRM1 mutational status is critical to G2/M checkpoint maintenance. Moreover, we found that the ability of PBRM1 deficiency to predict response to immunotherapy correlates with expression of the cytosolic DNA-sensing pathway in clinical samples. These findings have implications for therapeutic responses in renal cancer.
Keywords
- SWI/SNF
- BAF
- PBRM1
- BAF180
- DREAM complex
- p21
- TP53
- G2/M checkpoint
- immunotherapy
- cGAS
- DNA damage
- inflammatory signaling
Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.349249.121.
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Freely available online through the Genes & Development Open Access option.
- Received December 7, 2021.
- Accepted July 13, 2022.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.