Regulating BRCA1 protein stability by cathepsin S-mediated ubiquitin degradation

Cell Death and Differentiation
SeoYoung KimYun-Sil Lee

Abstract

Cathepsin S (CTSS) is a cysteine protease that is thought to play a role in many physiological and pathological processes including tumor growth, angiogenesis, and metastasis; it has been identified as a radiation response gene. Here, we examined the role of CTSS in regulating the DNA damage response in breast cancer cells. Activating CTSS (producing the cleavage form of the protein) by radiation induced proteolytic degradation of BRCA1, which ultimately suppressed DNA double-strand break repair activity. Depletion of CTSS by RNAi or expression of a mutant type of CTSS enhanced the protein stability of BRCA1 by inhibiting its ubiquitination. CTSS interacted with the BRCT domain of BRCA1 and facilitated ubiquitin-mediated proteolytic degradation of BRCA1, which was tightly associated with decreased BRCA1-mediated DNA repair activity. Treatment with a pharmacological CTSS inhibitor inhibited proteolytic degradation of BRCA1 and restored BRCA1 function. Depletion of CTSS by shRNA delayed tumor growth in a xenograft mouse model, only in the presence of functional BRCA1. Spontaneously uced rat mammary tumors and human breast cancer tissues with high levels of CTSS expression showed low BRCA1 expression. From these data, we suggest t...Continue Reading

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Citations

Jun 20, 2019·Cell Cycle·Surinder M SoondAndrey A Zamyatnin
Sep 27, 2019·Frontiers in Immunology·Tanja JakošJanko Kos
Nov 7, 2019·Cancer Biomarkers : Section a of Disease Markers·Ewa KilarAnna Janocha
Nov 17, 2020·Frontiers in Oncology·Florentina DuicăDragoş-Valentin Predescu
Apr 1, 2021·Cell Reports·Elizabeth V MintenDavid S Yu
Jun 3, 2021·International Journal of Molecular Sciences·Victoria LiedtkeLysann Schenk
Apr 27, 2021·British Journal of Pharmacology·Liliana RaimundoLucília Saraiva

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Methods Mentioned

BETA
ubiquitination
immunoprecipitation
transfection
pull-down
FACS
xenograft
PCR
protein assay
fluorescence-activated cell sorting

Software Mentioned

Image J
GraphPad
GraphPad Prism

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