Mun, Gil-Im Choi, Eun Jin, Hee Choi, Seul-Ki Lee, Hanhee Kim, Seoyoung Kim, Junghyun Kang, Chaerin Oh, Hye Lim Lee, Hae-June Ahn, Dae-Ro Lee, Yun-Sil 2024-10-26T15:30:05Z 2024-10-26T15:30:05Z 2024-10-25 2025-01 0925-4439 https://pubs.kist.re.kr/handle/201004/150882 There is evidence that BRCA1, particularly cytoplasmic BRCA1, plays a significant role in initiating apoptosis through various mechanisms. Maintaining the stability of BRCA1 in cancer cells may be a promising therapeutic strategy for breast cancer, especially in cases of triple-negative breast cancer (TNBC) lacking appropriate therapeutic targets. Previously, it was reported that cathepsin S (CTSS) interacts with the BRCT domain of BRCA1, leading to ubiquitin-mediated degradation. We further investigated the critical role of BRCA1 phosphorylation at Ser1387, which is mediated by ionizing radiation (IR)-induced activation of ATM. This phosphorylation event was identified as a key factor in CTSS-mediated ubiquitin degradation of BRCA1. The functional inhibition of CTSS, using small molecules or a knockdown system, sensitized TNBC cells when exposed to IR by restoring the stability of cytoplasmic BRCA1. The increase in cytoplasmic BRCA1 led to the degradation of anti-apoptotic BCL2, which was responsible for the radiosensitization effect observed with CTSS inhibition. These results suggest that inhibiting CTSS may be an effective strategy for radiosensitization in TNBC cells through BCL2 degradation that is mediated by inhibition of CTSS-induced BRCA1 degradation. English Elsevier BV Phosphorylation of BRCA1 at serine 1387 plays a critical role in cathepsin S-mediated radiation resistance via BRCA1 degradation and BCL2 stabilization Article 10.1016/j.bbadis.2024.167523 1 Biochimica et Biophysica Acta - Molecular Basis of Disease, v.1871, no.1 Biochimica et Biophysica Acta - Molecular Basis of Disease 1871 1 Y scie scopus 001329595300001 2-s2.0-85205223589 Biochemistry & Molecular Biology Biophysics Cell Biology Biochemistry & Molecular Biology Biophysics Cell Biology Article NEGATIVE BREAST-CANCER TUMOR-SUPPRESSOR ATM CHECKPOINT APOPTOSIS KINASE