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

  • Cell Signal. 2021 Nov;87:110106. doi: 10.1016/j.cellsig.2021.110106.
Ramazan Gundogdu  1 ,  M Kadir Erdogan  2 ,  Angeliki Ditsiou  3 ,  Victoria Spanswick  4 ,  Juan Jose Garcia-Gomez  4 ,  John A Hartley  4 ,  Fumiko Esashi  5 ,  Alexander Hergovich  6 ,  Valenti Gomez  7
Affiliations
  • 1. Department of Biology, Bingol University, Bingol 12000, Turkey; UCL Cancer Institute, University College London, London WC1E 6DD, UK. Electronic address: [email protected].
  • 2. Department of Biology, Bingol University, Bingol 12000, Turkey.
  • 3. Department of Biochemistry and Biomedicine, University of Sussex, Brighton BN1 9QG, UK; UCL Cancer Institute, University College London, London WC1E 6DD, UK.
  • 4. UCL Cancer Institute, University College London, London WC1E 6DD, UK.
  • 5. Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
  • 6. UCL Cancer Institute, University College London, London WC1E 6DD, UK; Evotec France, Toulouse 31100, France.
  • 7. UCL Cancer Institute, University College London, London WC1E 6DD, UK. Electronic address: [email protected].
PMID: 34363951 DOI: 10.1016/j.cellsig.2021.110106
Abstract

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.

Keywords
DNA damage response signalling; Homologous recombination DNA repair; Mps one binder 2 (MOB2); Personalised PARP inhibitor treatments.
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