Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development

XRCC4 is a non-homologous end-joining protein employed in DNA double strand break repair and in V(D)J recombination(1,2). In mice, XRCC4-deficiency ca uses a pleiotropic phenotype, which includes embryonic lethality and massiv e neuronal apoptosis 2. When DNA damage is not repaired, activation of the cell cycle checkpoint protein p53 can lead to apoptosis(3). Here we show th at p53-deficiency rescues several aspects of the XRCC4-deficient phenotype, including embryonic lethality, neuronal apoptosis, and impaired cellular p roliferation. However, there was no significant rescue of impaired V(D)J re combination or lymphocyte development. Although p53-deficiency allowed post natal survival of XRCC4-deficient mice, they routinely succumbed to pro-B-c ell lymphomas which had chromosomal translocations linking amplified c-myc oncogene and IgH locus sequences. Moreover, even XRCC4-deficient embryonic fibroblasts exhibited marked genomic instability including chromosomal tran slocations. Our findings support a crucial role for the non-homologous end- joining pathway as a caretaker of the mammalian genome, a role required bot h for normal development and for suppression of tumours.