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.

Keywords: DNA damage response; MRN complex; chemotherapy; radiotherapy; tumorigenesis.

Fig. 1

Structure and conformation of MRN complex. a Key domains of MRN complex subunits. Phosphoesterase domain of MRE11 has both single strand DNA endonuclease and double strand DNA exonuclease activity. Antiparallel coiled-coil domain of RAD50 extends the protein. Zinc hook domain of RAD50 facilitates the formation of dimers as depicted in (b). b MRN complex goes through conformational changes when ABC-ATPase domains (A/B Walker motifs) binds to ATP and forms a head-to-tail dimer. This compact, rigid, and closed conformation blocks access to MRE11 active sites. Upon hydrolysis and removing of ATP, MRN complex switches to an open form, exposing the active sites of MRE11. (FHA: fork-head associated domain; BRCT: breast cancer-associated 1 C domain)

Fig. 2

DNA binding and processing function of MRN complex. a-b Vertical view of MRE11 complex holding synaptic DNA complex (a) and branched DNA (b). Two MRE11 subunits are oriented symmetrically and bind the synaptic DNA complex which is normally seen in HR (a). In collapsed replication fork, branched DNA is hold in MRE11 complex asymmetrically in one half of the MRE11 dimeric cleft (b). c-d Models for MRN complex in processing DNA ends. For initiation of HR, MRN complex binds sister chromatid with broken DNA through a tail-to-tail link with another MRN complex and prepares for the further procedure of HR (c). In NHEJ, two MRN complexes bind the two ends of broken DNA separately. Later, through structure transition, MRN complexes tether and align broken ends for subsequent repair steps (d)