hMOB2 deficiency impairs homologous recombination-mediated DNA repair and sensitises cancer cells to PARP inhibitors

Journal article

Monopolar spindle-one binder (MOBs) proteins are evolutionarily conserved and contribute to various cellular signalling pathways. Recently, we reported that hMOB2 functions in preventing the accumulation of endogenous DNA damage and a subsequent p53/p21-dependent G1/S cell cycle arrest in untransformed cells. However, the question of how hMOB2 protects cells from endogenous DNA damage accumulation remained enigmatic. Here, we uncover hMOB2 as a regulator of double-strand break (DSB) repair by homologous recombination (HR). hMOB2 supports the phosphorylation and accumulation of the RAD51 recombinase on resected single-strand DNA (ssDNA) overhangs. Physiologically, hMOB2 expression supports cancer cell survival in response to DSB-inducing anti-cancer compounds. Specifically, loss of hMOB2 renders ovarian and other cancer cells more vulnerable to FDA-approved PARP inhibitors. Reduced MOB2 expression correlates with increased overall survival in patients suffering from ovarian carcinoma. Taken together, our findings suggest that hMOB2 expression may serve as a candidate stratification biomarker of patients for HR-deficiency targeted cancer therapies, such as PARP inhibitor treatments.

Authors: Gundogdu, R; Erdogan, MK; Ditsiou, A; Spanswick, V; Garcia-Gomez, JJ

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Cellular Signalling
• Volume: 87
• Article number: 110106
• Place of publication: England
• Publication date: 2021-08-05
• Acceptance date: 2021-08-02
• DOI: 10.1016/j.cellsig.2021.110106
• EISSN: 1873-3913
• ISSN: 0898-6568
• Pmid: 34363951
• Language: English
• Keywords: Mps one binder 2 (MOB2); homologous recombination DNA repair; FFR; DNA damage response signalling; prsonalised PARP inhibitor treatments