ATLD-derived MRE11 variant enhances radiation-induced intestinal tumorigenesis in ApcMin/+ mice

The MRE11-RAD50-NBS1 (MRN) protein complex plays a key role in the DNA damage response by activating ATM signaling. While biallelic variants in the MRE11 gene cause ataxia telangiectasia-like disorder (ATLD) with variable characteristics, including ataxia, dystonia, dysarthria, and increased sensitivity to ionizing radiation, their effects on cancer predisposition are not clearly established. Here, we describe an ATLD patient with compound heterozygous variants c.658 A >C, an exon-skipping splicing variant, and c.140 C > T (A47V). His patient-derived lymphoblastoid cell lines exhibited increased chromosomal radiosensitivity compared with the parental and healthy control cells. We generated a knock-in mouse with the Mre11 A47V variant that recapitulated the key features of ATLD model mice, including reduced expression levels of MRN complex proteins, altered γH2AX kinetics following irradiation, increased chromosomal radiosensitivity, and impaired fertility in homozygous females. To assess the impact of the Mre11 A47V variant on susceptibility to radiation-induced tumorigenesis, Mre11 A47V Apc Min/+ compound mutant mice were generated and exposed to γ-irradiation (2 Gy) at 2 weeks old. Homozygous A47V Apc Min/+ mice exhibited higher small intestine tumor multiplicity compared with heterozygous and wild-type mice, especially in the irradiated group. These results are consistent with a model in which MRN impairment enhances susceptibility to radiation-induced tumorigenesis in vivo under defined genetic and exposure conditions.