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

DNA Repair (Amst). 2017 Jun;54:40-45. doi: 10.1016/j.dnarep.2017.04.001. Epub 2017 Apr 10.

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.

Keywords: DNA polymerase mu; DSB; Genomic instability; Lymphoma; NHEJ; Polμ; Sarcoma; p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis*
  • Carrier Proteins / genetics
  • Cyclin-Dependent Kinase 4 / genetics
  • DNA / metabolism
  • DNA Copy Number Variations
  • DNA End-Joining Repair*
  • DNA-Directed DNA Polymerase / genetics*
  • Gene Amplification
  • Gene Deletion
  • Genomic Instability
  • Lymphoma / genetics
  • Lymphoma / metabolism
  • Lymphoma / pathology
  • Mice
  • Mice, Knockout
  • Sarcoma / genetics
  • Sarcoma / metabolism*
  • Sarcoma / pathology
  • Tumor Suppressor Protein p53 / genetics*
  • Up-Regulation

Substances

  • Carrier Proteins
  • Kub3 protein, mouse
  • Tumor Suppressor Protein p53
  • DNA
  • Cdk4 protein, mouse
  • Cyclin-Dependent Kinase 4
  • DNA polymerase mu
  • DNA-Directed DNA Polymerase