The DNA damage sensor protein NBN: role of BRCT domains in the DNA damage response

""The integrity of the genome is of primary importance for its stability. The BRCA1 Carboxy-. Terminal (BRCT) tandem domains are present in more than 50 proteins involved in the response to. the DNA double-strand breaks (DSBs) sensing and signaling (e.g., NBN, 53BP1, BRCA1, and. MDC1). These domains are pivotal in phosphorylation-dependent protein-protein recognition, and. epidemiological data indicate a relationship between mutations within BRCT domains and cancer. susceptibility.. The NBN protein, together with MRE11 and RAD50, forms a trimer involved in nearly. every aspect of DNA damage response (DDR), including sensing, signaling, and repair of DNA. lesions. To date, the exact role of NBN BRCT domains in all these phases is still matter of debate,. and controversial data are available in the literature regarding protein-protein interaction and timing. of BRCT-containing proteins localization on the DSB.. To study the role of the tandem BRCT domains of NBN in the DDR, natural and artificial. NBN mutations, all perturbing the relative geometry of the two BRCT domains, have been studied. by a combined biochemical and cell-biological approach. In particular, DNA damage sensing,. protein-protein interaction, and activation of DNA damage pathways have been addressed in order. to assess how tandem BRCT domains may influence the overall cellular metabolism, with possible. consequences on cancer development.. Results obtained indicate that both missense and truncating mutations within BRCT domains. of NBN affect the proper activation of the DDR, altering the localization of repair proteins at the. DSB, as well as DNA damage signaling. Overall, these data further clarify the molecular bases for. the severe phenotype observed in patients affected by the Nijmegen breakage syndrome, carrying. mutations within the BRCT domain of NBN protein""