Haploinsufficiency of the mSds3 chromatin regulator promotes chromosomal instability and cancer only upon complete neutralization of p53

David S. Geller, J. H. Dannenberg, N. Simpson, P. M. Finnerty, L. Miao, G. M. Turner, Z. Ding, R. Carrasco, R. A. DePinho

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The mSin3 corepressor complex has been linked to diverse cancer signaling pathways through its capacity to regulate target gene expression via chromatin modification. mSds3, a cell essential gene, is a key component of the mSin3 complex serving to maintain its inherent histone deacetylase activity. mSds3 also serves an essential role in the establishment of pericentric heterochromatin, and genetic ablation of mSds3 results in chromosome missegregation. In contrast, mSin3A nullizygous cells show normal chromosome dynamics and cytogenetic profiles. The integral role of mSds3 in controlling chromosome segregation and mSin3-regulated transcriptional networks prompted efforts to determine the neoplastic impact of loss of one copy of mSds3 or mSin3A. In particular, we assessed whether loss of one copy of mSds3, alone or in combination with p53 mutation, results in aneuploidy and promotes a cancer-prone condition in the mouse. We observe that, in a p53 null background, loss of one mSds3 allele results in accelerated tumor onset and increased tumor burden. Notably, these mSds3+/- p53-/- tumors exhibit a more complex cytogenetic profile characterized by marked aneuploidy and centromeric associations. The presence of even one copy of p53 is sufficient to suppress the accelerated tumorigenesis in mSds3+/- mice, consistent with a key role for p53 in monitoring mitotic fidelity. These observations with Sds3 mutant mice contrast with mSin3A+/- p53-/- mice, which do not show an accelerated or increased tumor incidence relative to mSin3A+/+p53-/- controls, correlating with the absence of aneuploidy detected upon mSin3A genetic inactivation. This genetic study establishes that the capacity of mSds3 to cooperate with p53 deficiency in cancer predisposition relates to its specific role in chromosome segregation, rather than its central role in maintaining a functional mSin3A complex.

Original languageEnglish (US)
Pages (from-to)7354-7360
Number of pages7
JournalOncogene
Volume25
Issue number56
DOIs
StatePublished - Nov 30 2006
Externally publishedYes

Fingerprint

Haploinsufficiency
Chromosomal Instability
Chromatin
Aneuploidy
Neoplasms
Chromosome Segregation
Cytogenetics
Chromosomes
Co-Repressor Proteins
Histone Deacetylases
Heterochromatin
Gene Regulatory Networks
Essential Genes
Tumor Burden
Carcinogenesis
Alleles
Gene Expression
Mutation
Incidence

Keywords

  • Aneuploidy
  • Chromatin
  • Histone deacetylase
  • Mouse model
  • mSin3
  • p53

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Haploinsufficiency of the mSds3 chromatin regulator promotes chromosomal instability and cancer only upon complete neutralization of p53. / Geller, David S.; Dannenberg, J. H.; Simpson, N.; Finnerty, P. M.; Miao, L.; Turner, G. M.; Ding, Z.; Carrasco, R.; DePinho, R. A.

In: Oncogene, Vol. 25, No. 56, 30.11.2006, p. 7354-7360.

Research output: Contribution to journalArticle

Geller, DS, Dannenberg, JH, Simpson, N, Finnerty, PM, Miao, L, Turner, GM, Ding, Z, Carrasco, R & DePinho, RA 2006, 'Haploinsufficiency of the mSds3 chromatin regulator promotes chromosomal instability and cancer only upon complete neutralization of p53', Oncogene, vol. 25, no. 56, pp. 7354-7360. https://doi.org/10.1038/sj.onc.1209734
Geller, David S. ; Dannenberg, J. H. ; Simpson, N. ; Finnerty, P. M. ; Miao, L. ; Turner, G. M. ; Ding, Z. ; Carrasco, R. ; DePinho, R. A. / Haploinsufficiency of the mSds3 chromatin regulator promotes chromosomal instability and cancer only upon complete neutralization of p53. In: Oncogene. 2006 ; Vol. 25, No. 56. pp. 7354-7360.
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AU - Miao, L.

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