Polμ deficiency induces moderate shortening of P53−/− mouse lifespan and modifies tumor spectrum

Abstract Non-homologous end joining (NHEJ) is the main mechanism for double strand break (DSB) DNA repair. The error-prone DNA polymerase mu ( Polμ ) is involved in immunoglobulin variable region rearrangement and in general, NHEJ in non-lymphoid cells. Deletion of NHEJ factors in P53 −/− mice, which are highly prone to development of T cell lymphoma, generally increases cancer incidence and shifts the tumor spectrum towards aggressive pro-B lymphoma. In contrast, Polμ deletion increased sarcoma incidence, proportionally reducing pro-B lymphoma development on the P53- deficient background. Array comparative genomic hybridization (aCGH) analyses showed DNA copy number alterations in both P53 −/− and Polμ −/− P53 −/− lymphomas. Our results also indicate that the increase in sarcoma incidence in Polμ −/− P53 −/− mice could be associated with Cdk4 and Kub3 amplification and overexpression. These results identify a role for Polμ in the prevention of sarcomagenesis on a murine P53- deficient background, in contrast to most other NHEJ factors.