@article{29f7dfd10c9f4db9b5982b1f18ca923c,
title = "BRCA1 mediates protein homeostasis through the ubiquitination of PERK and IRE1",
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",
author = "Robert Hromas and Gayathri Srinivasan and Ming Yang and Jaiswal, {Aruna S} and Totterdale, {Taylor A.} and Linda Phillips and Austin Kirby and Nazli Khodayari and Mark Brantley and Williamson, {Elizabeth A} and Kong, {Kimi Y.}",
note = "Funding Information: This research was supported by NIH R01 GM109645 , CA139429 , and CA205224 to RH; CPRIT Individual Investigator grant RP220269 to RH; NIH R01 GM084020 to EW, RH; Gatorade Trust Start-Up Fund 00123001 and Gatorade Pilot Project Award 00127907 to KYK. UT Health Start-Up Fund 163254-22100-M1522 to RH, KYK. Lori Zabar Women{\textquoteright}s Health Research Award of the Foundation for Women{\textquoteright}s Wellness to KYK. Confocal images were generated in the Core Optical Imaging Facility which is supported by UTHSCSA and NIH- NCI P30 CA54174 ( CTRC at UTHSCSA). We would also like to thank the support from UF IACUC and the animal facility staff for the animal study. Funding Information: This research was supported by NIH R01 GM109645, CA139429, and CA205224 to RH; CPRIT Individual Investigator grant RP220269 to RH; NIH R01 GM084020 to EW, RH; Gatorade Trust Start-Up Fund 00123001 and Gatorade Pilot Project Award 00127907 to KYK. UT Health Start-Up Fund 163254-22100-M1522 to RH, KYK. Lori Zabar Women's Health Research Award of the Foundation for Women's Wellness to KYK. Confocal images were generated in the Core Optical Imaging Facility which is supported by UTHSCSA and NIH-NCI P30 CA54174 (CTRC at UTHSCSA). We would also like to thank the support from UF IACUC and the animal facility staff for the animal study. Conceptualization, K.Y.K.; experiments, G.S, M.Y. A.J. T.A.T. L.P. A.K. and N.K.; data analysis, R.H. G.S. A.J. N.K. M.B. E.A.W. and K.Y.K.; writing – initial draft, K.Y.K.; writing – review and editing, R.H. E.A.W. and K.Y.K. The authors declare no competing interests. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = dec,
day = "22",
doi = "10.1016/j.isci.2022.105626",
language = "English (US)",
volume = "25",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
number = "12",
}