Abstract
The MRE11-RAD50-NBS1 (MRN) protein complex is one of the primary vehicles for repairing DNA double strand breaks and maintaining the genomic stability within the cell. The role of the MRN complex to recognize and process DNA double-strand breaks as well as signal other damage response factors is critical for maintaining proper cellular function. Mutations in any one of the components of the MRN complex that effect function or expression of the repair machinery could be detrimental to the cell and may initiate and/or propagate disease. Here, we discuss, in a structural and biochemical context, mutations in each of the three MRN components that have been associated with diseases such as ataxia telangiectasia-like disorder (ATLD), Nijmegen breakage syndrome (NBS), NBS-like disorder (NBSLD) and certain types of cancers. Overall, deepening our understanding of disease-causing mutations of the MRN complex at the structural and biochemical level is foundational to the future aim of treating diseases associated with these aberrations.
Highlights
Genomic DNA within a cell experiences hundreds of spontaneous damaging events per day.The various forms of DNA damage include DNA base lesions, DNA-DNA crosslinks, DNA-protein crosslinks, and single- and double-strand breaks (DSBs)
Due to the various roles MRN has in maintaining the integrity of the genomic DNA, mutations affecting the nuclease activity, structure, or expression levels of MRE11 have been correlated with immunodeficiency, sensitivity to ionizing radiation (IR), and/or oncogenesis (Table 1)
ataxia telangiectasia-like disorder (ATLD), an autosomal recessive disease characterized by higher sensitivity to ionizing radiation, developmental disorders, immunodeficiency, and neuronal and cerebellar degeneration, is often caused by mutation in MRE11 that leads to lower levels of the enzyme or an inability to interact with
Summary
Genomic DNA within a cell experiences hundreds of spontaneous damaging events per day. Cells rely on a number of specific, multilayered systems to detect and repair these DNA lesions. These are collectively called the DNA damage response (DDR) and are composed of ~200 proteins that either act directly in repair or have a supporting role. Mutation of DDR genes resulting in altered protein expression and/or function have been associated with cancer and other diseases [1,2,3,4,5]. The MRE11-RAD50-NBS1/Xrs (MRN in humans or MRX in yeast) protein complex is one of the first responders to DNA DSBs and is the primary complex to recognize, signal, and assist in the repair of these lesions [6,7,8]. We will outline many of the currently known disease-related mutations in the MRN genes and describe the physical, biochemical, and structural information reported in the literature for each
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