Analysis of Wild-Type and Mutant SL3-3 Murine Leukemia Virus Insertions in the c- myc Promoter during Lymphomagenesis Reveals Target Site Hot Spots, Virus-Dependent Patterns, and Frequent Error-Prone Gap Repair

Author:

Nielsen Anne Ahlmann1,Sørensen Annette Balle1,Schmidt Jörg2,Pedersen Finn Skou13

Affiliation:

1. Department of Molecular Biology

2. Department of Comparative Medicine, GSF-National Research Center for Environment and Health, Neuherberg, Germany

3. Department of Medical Microbiology and Immunology, University of Aarhus, Aarhus, Denmark

Abstract

ABSTRACT The murine leukemia retrovirus SL3-3 induces lymphomas in the T-cell compartment of the hematopoetic system when it is injected into newborn mice of susceptible strains. Previously, our laboratory reported on a deletion mutant of SL3-3 that induces T-cell tumors faster than the wild-type virus (S. Ethelberg, A. B. Sørensen, J. Schmidt, A. Luz, and F. S. Pedersen, J. Virol. 71:9796-9799, 1997). PCR analyses of proviral integrations in the promoter region of the c- myc proto-oncogene in lymphomas induced by wild-type SL3-3 [SL3-3(wt)] and the enhancer deletion mutant displayed a difference in targeting frequency into this locus. We here report on patterns of proviral insertions into the c- myc promoter region from SL3-3(wt), the faster variant, as well as other enhancer variants from a total of approximately 250 tumors. The analysis reveals (i) several integration site hot spots in the c- myc promoter region, (ii) differences in integration patterns between SL3-3(wt) and enhancer deletion mutant viruses, (iii) a correlation between tumor latency and the number of proviral insertions into the c- myc promoter, and (iv) a [5′-(A/C/G)TA(C/G/T)-3′] integration site consensus sequence. Unexpectedly, about 12% of the sequenced insertions were associated with point mutations in the direct repeat flanking the provirus. Based on these results, we propose a model for error-prone gap repair of host-provirus junctions.

Publisher

American Society for Microbiology

Subject

Virology,Insect Science,Immunology,Microbiology

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