Involvement of ATMIN-DYNLL1-MRN axis in the progression and aggressiveness of serous ovarian cancer

The loss of DYNLL1 contributes to chemoresistance in ovarian cancer. DYNLL1 binds to MRE11, a component of MRN complex (MRE11-RAD50-NBS1), and limits its function in homologous recombination (HR) repair in BRCA1-mutant cells. Decreased activity of MRE11 results in less HR-repair events and thus leads to higher sensitivity against DNA-damaging agents such as cisplatin. Therefore, a better understanding of the cellular changes in DYNLL1-MRN axis in ovarian cancer is needed. Here, we showed that DYNLL1 overexpression leads to decreased chemoresistance even in BRCA-proficient ovarian cancer cells. ATMIN, a transcriptional activator of DYNLL1, showed decreased expression; however, two components of MRN complex, MRE11 and NBS1 (NBN), showed increased expression in high grade compared to low grade serous ovarian cancer. We found that the components of MRN complex (MRE11-RAD50-NBS1) have higher protein levels in sites of omental metastasis and serous tubal intraepithelial carcinoma (STIC) compared to surrounding non-malignant stromal cells in patients with high grade serous ovarian cancer. We showed that the percentage of copy number variation (CNV) events in genes encoding ATMIN, DYNLL1, MRE11 and NBN are the highest in ovarian cancer among other cancer types. ATMIN and DYNLL1 genes are mostly characterized by copy number losses; however, CNV events in MRN complex components are mostly copy number gains. This study highlights the importance of ATMINDYNLL1-MRN axis in the development, progression and therapy response of ovarian cancer. MRN levels in ovarian cancer that differ from adjacent, non-malignant tissues may represent actionable therapeutic vulnerabilities. (c) 2021 Elsevier Inc. All rights reserved.

Automated summary

Loss of DYNLL1 contributes to chemoresistance in ovarian cancer, while overexpression of DYNLL1 leads to decreased chemoresistance. Components of the MRN complex, MRE11 and NBS1, show increased expression in high grade serous ovarian cancer, highlighting the importance of the ATMINDYNLL1-MRN axis in the development, progression, and therapy response of ovarian cancer.