Importance of Germline and Somatic Alterations in Human MRE11, RAD50, and NBN Genes Coding for MRN Complex

Abstract

The MRE11, RAD50, and NBN genes encode for the nuclear MRN protein complex, which senses the DNA double strand breaks and initiates the DNA repair. The MRN complex also participates in the activation of ATM kinase, which coordinates DNA repair with the p53-dependent cell cycle checkpoint arrest. Carriers of homozygous germline pathogenic variants in the MRN complex genes or compound heterozygotes develop phenotypically distinct rare autosomal recessive syndromes characterized by chromosomal instability and neurological symptoms. Heterozygous germline alterations in the MRN complex genes have been associated with a poorly-specified predisposition to various cancer types. Somatic alterations in the MRN complex genes may represent valuable predictive and prognostic biomarkers in cancer patients. MRN complex genes have been targeted in several next-generation sequencing panels for cancer and neurological disorders, but interpretation of the identified alterations is challenging due to the complexity of MRN complex function in the DNA damage response. In this review, we outline the structural characteristics of the MRE11, RAD50 and NBN proteins, the assembly and functions of the MRN complex from the perspective of clinical interpretation of germline and somatic alterations in the MRE11, RAD50 and NBN genes.

Interactions between the DNA Damage Response and the Telomere Complex in Carcinogenesis: A Hypothesis

“…This study confirmed the well-known fact that mutations in Mre11 are associated with the reduction or loss of other proteins of the MRN complex, which makes the specific role of Mre11 in cancer predisposition even more elusive [ 75 ]. However, the occurrence of germline Mre11 alterations in a minority of breast cancer patients observed in these studies has not been confirmed in ample case population studies [ 70 ]. It has also been suggested that mutations in Mre11 are associated with increased susceptibility to colorectal cancer.…”

“…Similar to AT, cells derived from patients with NBS exhibit accelerated shortening of telomeres, loss of intra-S and G2/M checkpoint control, and genomic instability [ 69 ]. Another study including 241 cases reported a median age of cancer onset of 9.1 years with a probability of 20-year survival of 44.6% [ 70 ], whereas a murine model in which exons 4 and 5 were replaced by neo did not show increased tumor incidence [ 71 ]. Dumon-Jones et al generated heterozygous knockout (Nbn +/− ) mice that developed a wide array of tumors in addition to lymphomas and gamma-radiation-enhanced tumor development [ 72 ].…”

Phase separation in DNA double-strand break response

“…Once a DSB occurs, MRN complex recognizes damaged DNA and initiates a signaling cascade to activate cellular response to repair the break [ 38 ]. MRN complex facilitates autophosphorylation of ataxia telangiectasia mutated (ATM) at serine 1981 (S1981) and autoacetylation of ATM at lysine 3106 (K3106) [ 39 , 40 ].…”

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“…Specifically, Otahalova et al [ 7 ] outline the structural characteristics of the MRE11, RAD50, and NBN proteins and the assembly and functions of the MRN complex from the perspective of clinical interpretation of germline and somatic alterations in the MRE11, RAD50, and NBN genes. They describe the structure of the MRN Complex and its function in double-strand break (DSB) repair and analyze the different germline alterations of the MRN complex genes in autosomal recessive syndromes, as well as the association between heterozygous germline alterations in these genes and cancer predisposition.…”

“…They describe the structure of the MRN Complex and its function in double-strand break (DSB) repair and analyze the different germline alterations of the MRN complex genes in autosomal recessive syndromes, as well as the association between heterozygous germline alterations in these genes and cancer predisposition. Their review finally explores the role of somatic alterations in the MRN complex genes in different tumors [ 7 ].…”