PBRM1 regulates the stress response in epithelial cells

Abstract

Polybromo1 (PBRM1) is a chromatin remodeler subunit highly mutated in cancer, particularly renal clear cell carcinoma. PBRM1 is a member of the SWI/SNF subcomplex, PBAF (PBRM1-Brg1/Brm Associated Factors) and is characterized by six tandem bromodomains. Here we establish a role for PBRM1 in epithelial cell maintenance through the expression of genes involved in cell adhesion, metabolism, stress response, and apoptosis. In support of a general role for PBRM1 in stress response and apoptosis, we observe that loss of PBRM1 results in an increase in reactive oxygen species generation and a decrease in cellular viability under stress conditions. We find that loss of PBRM1 promotes cell growth under favorable conditions but is required for cell survival under conditions of cellular stress.

PBRM1 Deficiency Confers Synthetic Lethality to DNA Repair Inhibitors in Cancer

“…As SETX is also recruited at sites of DNA DSBs in transcriptionally active loci (56), a transcriptional stress-dependent sensitivity to DNA repair inhibitors represents a second alternative model. This secondary model is consistent with the previously described role of PBRM1 in regulating the transcription of stress response genes and in mediating the cytoprotective effects against endogenous oncogenic, replicative stresses (57,58), or exogenous stresses (59). A third alternative model to explain the PBRM1/DNA repair inhibitors synthetic lethality may be that PBRM1, which contributes to replication fork re-priming through PCNA recruitment (6), might also interact with other chromatin remodelers that are ATR substrates and promote replication fork repair, such as the SWI/SNF-family member SMARCAL1 (60).…”