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The regulation of DNA damage signalling and repair by MOB2

Gundogdu, R; (2016) The regulation of DNA damage signalling and repair by MOB2. Doctoral thesis , UCL (University College London).

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Abstract

Human MOB2 (hMOB2) is a member of the highly conserved MOB protein family. MOBs have essential functions as regulators of diverse signalling pathways. In this regard, a recent genome wide screen for novel players in the DNA damage response (DDR) suggested hMOB2 as a potential candidate awaiting validation of its potential role in the DDR. Therefore, as the DDR is critical to maintain genomic integrity and to prevent tumorigenesis, my PhD project focused on understanding the involvement of hMOB2 in the DDR. Significantly, we found that in normal growth conditions hMOB2 is required to prevent the accumulation of unrepaired DNA doublestrand breaks (DSBs) in untransformed proliferating human cells. hMOB2 supports cell cycle checkpoint activation, DDR signalling, and cell survival upon exposure to exogenously induced DNA damage. Surprisingly, these novel functions of hMOB2 appear to be linked with the MRE11-RAD50-NBS1 (MRN) complex, since hMOB2 interacts with RAD50 and supports the recruitment of the MRN and activated ATM to damaged chromatin. Equally important, hMOB2-deficient cells display impaired DSB repair by homologous recombination repair (HRR) as judged by GFP-recombination assays and RAD51 foci formation. Remarkably, hMOB2 knockdown compromises PLK1-mediated phosphorylation of RAD51, which is significant for ssDNA-RAD51 nucleofilament stabilisation. Strikingly, our research further revealed that defective HRR due to hMOB2 knockdown may provide a novel translational approach for future clinical studies. Notably, hMOB2 knockdown sensitises human tumour cells to inter-strand crosslinking (ICL) chemotherapeutics and poly (ADP-ribose) polymerase (PARP) inhibitors. Considering further that the human MOB2 gene appears to display loss of heterozygosity in more than 50% of testicular, bladder, cervical, ovarian and lung carcinomas, our findings cumulatively propose that hMOB2 expression may be considered as a candidate biomarker in the evaluation for targeted therapies of cancer with defective HRR.

Type: Thesis (Doctoral)
Title: The regulation of DNA damage signalling and repair by MOB2
Event: UCL
Language: English
Additional information: Third party copyright material has been removed from ethesis.
URI: http://discovery.ucl.ac.uk/id/eprint/1528649
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