PBAF loss leads to DNA damage-induced inflammatory signaling through defective G2/M checkpoint maintenance.
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Authors
Feng, H
Lane, KA
Roumeliotis, TI
Jeggo, PA
Somaiah, N
Choudhary, JS
Downs, JA
Lane, KA
Roumeliotis, TI
Jeggo, PA
Somaiah, N
Choudhary, JS
Downs, JA
Document Type
Journal Article
Date
2022-07-28
Date Accepted
2022-07-13
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.
Citation
Genes and Development, 2022,
Source Title
Genes and Development
Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
ISSN
0890-9369
eISSN
1549-5477
1549-5477
1549-5477
Collections
Research Team
Trans Breast Radiobiol
Genome Stability
Genome Stability