BRCA1 mediates protein homeostasis through the ubiquitination of PERK and IRE1

Robert Hromas; Gayathri Srinivasan; Ming Yang; Aruna Jaiswal; Taylor A Totterdale; Linda Phillips; Austin Kirby; Nazli Khodayari; Mark Brantley; Elizabeth A Williamson; Kimi Y Kong

doi:10.1016/j.isci.2022.105626

BRCA1 mediates protein homeostasis through the ubiquitination of PERK and IRE1

iScience. 2022 Nov 19;25(12):105626. doi: 10.1016/j.isci.2022.105626. eCollection 2022 Dec 22.

Authors

Robert Hromas^{1

2}, Gayathri Srinivasan^{1

2}, Ming Yang^{1

3}, Aruna Jaiswal^{1

2}, Taylor A Totterdale², Linda Phillips¹, Austin Kirby^{1

2}, Nazli Khodayari⁴, Mark Brantley⁴, Elizabeth A Williamson^{1

2}, Kimi Y Kong^{1

2}

Affiliations

¹ Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229, USA.
² Department of Medicine and the Cancer Center, University of Florida Health, Gainesville, FL 32610, USA.
³ Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha 410013, China.
⁴ Department of Medicine, Alpha-1 Research Program, University of Florida Health, Gainesville, FL 32610, USA.

Abstract

Tumors with BRCA1 mutations have poor prognoses due to genomic instability. Yet this genomic instability has risks and BRCA1-deficient (def) cancer cells must develop pathways to mitigate these risks. One such risk is the accumulation of unfolded proteins in BRCA1-def cancers from increased mutations due to their loss of genomic integrity. Little is known about how BRCA1-def cancers survive their genomic instability. Here we show that BRCA1 is an E3 ligase in the endoplasmic reticulum (ER) that targets the unfolded protein response (UPR) stress sensors, Eukaryotic Translation Initiation Factor 2-alpha Kinase 3 (PERK) and Serine/Threonine-Protein Kinase/Endoribonuclease Inositol-Requiring Enzyme 1 (IRE1) for ubiquitination and subsequent proteasome-mediated degradation. When BRCA1 is mutated or depleted, both PERK and IRE1 protein levels are increased, resulting in a constitutively activated UPR. Furthermore, the inhibition of protein folding or UPR signaling markedly decreases the overall survival of BRCA1-def cancer cells. Our findings define a mechanism used by the BRCA1-def cancer cells to survive their increased unfolded protein burden which can be used to develop new therapeutic strategies to treat these cancers.

Keywords: Cancer; Cell biology; Functional aspects of cell biology.

Abstract

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