MRE11-RAD50-NBS1 complex alterations and DNA damage response: implications for cancer treatment

Abstract

Genome instability is a hallmark of cancer cells and can be accelerated by defects in cellular responses to DNA damage. This feature of malignant cells opens new avenues for tumor targeted therapy. MRE11-RAD50-NBS1 complex plays a crucial role in sensing and repair of DNA damage. Through interacting with other important players of DNA damage response, MRE11-RAD50-NBS1 complex is engaged in various DNA damage repair pathways. Mutations in any member of this complex may lead to hypersensitivity to genotoxic agents and predisposition to malignancy. It is assumed that the defects in the complex may contribute to tumorigenesis and that treatments targeting the defect may be beneficial to cancer patients. Here, we summarized the recent research findings of the role of MRE11-RAD50-NBS1 complex in tumorigenesis, cancer treatment and discussed the potential approaches of targeting this complex to treat cancer.

Identification of Novel BRCA1 and RAD50 Mutations Associated With Breast Cancer Predisposition in Tunisian Patients

“…Using whole exome sequencing, we also identified a rare exonic VUS on RAD50 (c.3647C > G, rs1314725075, MAF = 4.061 × 10 –06 ) in a breast cancer patient originating also from the North Eastern Tunisian region. Accumulating evidence indicates that RAD50 is a breast cancer susceptibility gene associated with genomic instability ( Heikkinen et al, 2003 , 2006 ; Hsu et al, 2007 ; Damiola et al, 2014 ; Kleibl and Kristensen, 2016 ; Kim et al, 2017 ; Bian et al, 2019 ). Indeed, RAD50 is part of the MRE11/RAD50/NBN (MRN) complex that plays a key role in detecting DNA double-strand breaks, recruiting and activating Ataxia-Telangiectasia Mutated protein (ATM) and in processing the DNA repair pathway ( Bian et al, 2019 ; Situ et al, 2019 ).…”

“…Indeed, RAD50 is part of the MRE11/RAD50/NBN (MRN) complex that plays a key role in detecting DNA double-strand breaks, recruiting and activating Ataxia-Telangiectasia Mutated protein (ATM) and in processing the DNA repair pathway ( Bian et al, 2019 ; Situ et al, 2019 ). Mutations in one or more genes forming this complex may lead to hypersensitivity to genotoxic agents and predisposition to malignancy ( Bian et al, 2019 ).…”

A Survey of Reported Disease-Related Mutations in the MRE11-RAD50-NBS1 Complex

“…Therapeutically controlling the activity of MRN could present an option for the treatment of certain cancer types, where orthologous DNA damage repair pathways are defective, through the synthetic lethality strategy. For example, there is interesting evidence that patients with endometrial cancer and mutations in MRE11 could be treated with PARP inhibitors [ 136 , 137 ]. Overall, understanding these mutations from a structural and biochemical standpoint will enhance our knowledge of the function of the MRN complex and may help in treating or preventing MRN-related diseases in the future.…”

Update on DNA-Double Strand Break Repair Defects in Combined Primary Immunodeficiency

“…The meiotic recombination 11 homologue 1 (MRE11), RAD50 and Nijmegen breakage syndrome protein 1 (NBS1) proteins play a pivotal role in sensing DNA-dsb and coordinating the response to initiate cell cycle checkpoint arrest and commence DNA repair or initiate apoptosis. This compound (the MRN complex), which exhibits dual single strand DNA endonuclease and double strand DNA exonuclease activity, comes together as a heterodimer complex to execute three indispensable functions in DNA-dsb repair: binding and processing of damaged DNA securing DNA to bridge over short and long distance damage regions activation of DNA damage response and checkpoint signalling pathways [ 3 ] (Figure 1 ii). …”