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

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

Author information

1
Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), 28049 Madrid, Spain; Department of Regenerative Cardiology, Fundación Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
2
Department of Regenerative Cardiology, Fundación Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain; NIMGenetics SL, 28049 Madrid, Spain.
3
Animal Unit, Fundación Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain.
4
NIMGenetics SL, 28049 Madrid, Spain.
5
Centro de Biología Molecular Severo Ochoa (CBMSO), 28049 Madrid, Spain.
6
Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), 28049 Madrid, Spain; Department of Regenerative Cardiology, Fundación Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain; NIMGenetics SL, 28049 Madrid, Spain.
7
Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), 28049 Madrid, Spain; Department of Regenerative Cardiology, Fundación Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain. Electronic address: abernad@cnb.csic.es.

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

PMID:
28460268
DOI:
10.1016/j.dnarep.2017.04.001
[Indexed for MEDLINE]

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