Selection of reversions and suppressors of a mutation in the CBF binding site of a lymphomagenic retrovirus

Marita J. Martiney, Karen Rulli, Robert Beaty, Laura S. Levy, Jack Lenz

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The retrovirus SL3 induces T-cell lymphomas in mice. The transcriptional enhancer in the long terminal repeat (LTR) of SL3 contains two 72-bp repeats. Each repeat contains a binding site for the transcription factor CBF (also called AML1). The CBF binding sites are called core elements. SAA is a mutant that is identical to SL3 except for the presence of a single-base-pair substitution in each of the two core elements. This mutation significantly attenuates viral lymphomagenicity. Most lymphomas that occur in SAA-infected mice contain proviruses with reversions or second-site suppressor mutations within the core element. We examined the selective pressures that might account for the predominance of the reversions and suppressor mutations in tumor proviruses by analyzing when proviruses with altered core sequences became abundant during the course of lymphomagenesis. Altered core sequences were easily detected in thymus DNAs by 4 to 6 weeks after SAA infection of mice, well before lymphomas were grossly evident. This result is consistent with the hypothesis that viruses with the core sequence alterations emerged because they replicated more effectively in mice than SAA. The number of 72- bp tandem, repeats in the viral LTR was found to vary, presumably as a consequence of reverse transcriptase slippage during polymerization. Proviruses with two repeats predominated in the thymuses of SAA- and SL3- infected mice before lymphomas developed, although LTRs with one or three repeats were also present. This suggested that two was the optimal number of 72-bp repeats for viral replication. However, in iymphomas, proviruses with three or four repeats usually predominated. This suggested that a late step in the process of lymphomagenesis led to the abundance of proviruses with additional repeats. We hypothesize that proviruses with additional 72-bp repeats endowed the cells containing them with a selective growth advantage.

Original languageEnglish (US)
Pages (from-to)7599-7606
Number of pages8
JournalJournal of Virology
Volume73
Issue number9
StatePublished - 1999

Fingerprint

Retroviridae
Genetic Suppression
proviruses
Proviruses
binding sites
Binding Sites
lymphoma
mice
Lymphoma
terminal repeat sequences
Terminal Repeat Sequences
Thymus Gland
Tandem Repeat Sequences
tandem repeat sequences
RNA-directed DNA polymerase
T-Cell Lymphoma
RNA-Directed DNA Polymerase
virus replication
genetic suppression
Base Pairing

ASJC Scopus subject areas

  • Immunology

Cite this

Selection of reversions and suppressors of a mutation in the CBF binding site of a lymphomagenic retrovirus. / Martiney, Marita J.; Rulli, Karen; Beaty, Robert; Levy, Laura S.; Lenz, Jack.

In: Journal of Virology, Vol. 73, No. 9, 1999, p. 7599-7606.

Research output: Contribution to journalArticle

Martiney, Marita J. ; Rulli, Karen ; Beaty, Robert ; Levy, Laura S. ; Lenz, Jack. / Selection of reversions and suppressors of a mutation in the CBF binding site of a lymphomagenic retrovirus. In: Journal of Virology. 1999 ; Vol. 73, No. 9. pp. 7599-7606.
@article{f6841fc512b34b07a652f2b626ac106c,
title = "Selection of reversions and suppressors of a mutation in the CBF binding site of a lymphomagenic retrovirus",
abstract = "The retrovirus SL3 induces T-cell lymphomas in mice. The transcriptional enhancer in the long terminal repeat (LTR) of SL3 contains two 72-bp repeats. Each repeat contains a binding site for the transcription factor CBF (also called AML1). The CBF binding sites are called core elements. SAA is a mutant that is identical to SL3 except for the presence of a single-base-pair substitution in each of the two core elements. This mutation significantly attenuates viral lymphomagenicity. Most lymphomas that occur in SAA-infected mice contain proviruses with reversions or second-site suppressor mutations within the core element. We examined the selective pressures that might account for the predominance of the reversions and suppressor mutations in tumor proviruses by analyzing when proviruses with altered core sequences became abundant during the course of lymphomagenesis. Altered core sequences were easily detected in thymus DNAs by 4 to 6 weeks after SAA infection of mice, well before lymphomas were grossly evident. This result is consistent with the hypothesis that viruses with the core sequence alterations emerged because they replicated more effectively in mice than SAA. The number of 72- bp tandem, repeats in the viral LTR was found to vary, presumably as a consequence of reverse transcriptase slippage during polymerization. Proviruses with two repeats predominated in the thymuses of SAA- and SL3- infected mice before lymphomas developed, although LTRs with one or three repeats were also present. This suggested that two was the optimal number of 72-bp repeats for viral replication. However, in iymphomas, proviruses with three or four repeats usually predominated. This suggested that a late step in the process of lymphomagenesis led to the abundance of proviruses with additional repeats. We hypothesize that proviruses with additional 72-bp repeats endowed the cells containing them with a selective growth advantage.",
author = "Martiney, {Marita J.} and Karen Rulli and Robert Beaty and Levy, {Laura S.} and Jack Lenz",
year = "1999",
language = "English (US)",
volume = "73",
pages = "7599--7606",
journal = "Journal of Virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "9",

}

TY - JOUR

T1 - Selection of reversions and suppressors of a mutation in the CBF binding site of a lymphomagenic retrovirus

AU - Martiney, Marita J.

AU - Rulli, Karen

AU - Beaty, Robert

AU - Levy, Laura S.

AU - Lenz, Jack

PY - 1999

Y1 - 1999

N2 - The retrovirus SL3 induces T-cell lymphomas in mice. The transcriptional enhancer in the long terminal repeat (LTR) of SL3 contains two 72-bp repeats. Each repeat contains a binding site for the transcription factor CBF (also called AML1). The CBF binding sites are called core elements. SAA is a mutant that is identical to SL3 except for the presence of a single-base-pair substitution in each of the two core elements. This mutation significantly attenuates viral lymphomagenicity. Most lymphomas that occur in SAA-infected mice contain proviruses with reversions or second-site suppressor mutations within the core element. We examined the selective pressures that might account for the predominance of the reversions and suppressor mutations in tumor proviruses by analyzing when proviruses with altered core sequences became abundant during the course of lymphomagenesis. Altered core sequences were easily detected in thymus DNAs by 4 to 6 weeks after SAA infection of mice, well before lymphomas were grossly evident. This result is consistent with the hypothesis that viruses with the core sequence alterations emerged because they replicated more effectively in mice than SAA. The number of 72- bp tandem, repeats in the viral LTR was found to vary, presumably as a consequence of reverse transcriptase slippage during polymerization. Proviruses with two repeats predominated in the thymuses of SAA- and SL3- infected mice before lymphomas developed, although LTRs with one or three repeats were also present. This suggested that two was the optimal number of 72-bp repeats for viral replication. However, in iymphomas, proviruses with three or four repeats usually predominated. This suggested that a late step in the process of lymphomagenesis led to the abundance of proviruses with additional repeats. We hypothesize that proviruses with additional 72-bp repeats endowed the cells containing them with a selective growth advantage.

AB - The retrovirus SL3 induces T-cell lymphomas in mice. The transcriptional enhancer in the long terminal repeat (LTR) of SL3 contains two 72-bp repeats. Each repeat contains a binding site for the transcription factor CBF (also called AML1). The CBF binding sites are called core elements. SAA is a mutant that is identical to SL3 except for the presence of a single-base-pair substitution in each of the two core elements. This mutation significantly attenuates viral lymphomagenicity. Most lymphomas that occur in SAA-infected mice contain proviruses with reversions or second-site suppressor mutations within the core element. We examined the selective pressures that might account for the predominance of the reversions and suppressor mutations in tumor proviruses by analyzing when proviruses with altered core sequences became abundant during the course of lymphomagenesis. Altered core sequences were easily detected in thymus DNAs by 4 to 6 weeks after SAA infection of mice, well before lymphomas were grossly evident. This result is consistent with the hypothesis that viruses with the core sequence alterations emerged because they replicated more effectively in mice than SAA. The number of 72- bp tandem, repeats in the viral LTR was found to vary, presumably as a consequence of reverse transcriptase slippage during polymerization. Proviruses with two repeats predominated in the thymuses of SAA- and SL3- infected mice before lymphomas developed, although LTRs with one or three repeats were also present. This suggested that two was the optimal number of 72-bp repeats for viral replication. However, in iymphomas, proviruses with three or four repeats usually predominated. This suggested that a late step in the process of lymphomagenesis led to the abundance of proviruses with additional repeats. We hypothesize that proviruses with additional 72-bp repeats endowed the cells containing them with a selective growth advantage.

UR - http://www.scopus.com/inward/record.url?scp=0032816325&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032816325&partnerID=8YFLogxK

M3 - Article

VL - 73

SP - 7599

EP - 7606

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 9

ER -