Dynamic assembly of chromatin complexes during cellular senescence: Implications for the growth arrest of human melanocytic nevi

Debdutta Bandyopadhyay, Jonathan L. Curry, Qiushi Lin, Hunter W. Richards, Dahu Chen, Peter J Hornsby, Nikolai A. Timchenko, Estela E. Medrano

Research output: Contribution to journalArticle

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Abstract

The retinoblastoma (RB)/p16INK4a pathway regulates senescence of human melanocytes in culture and oncogene-induced senescence of melanocytic nevi in vivo. This senescence response is likely due to chromatin modifications because RB complexes from senescent melanocytes contain increased levels of histone deacetylase (HDAC) activity and tethered HDAC1. Here we show that HDAC1 is prominently detected in p16INK4a -positive, senescent intradermal melanocytic nevi but not in proliferating, recurrent nevus cells that localize to the epidermal/dermal junction. To assess the role of HDAC1 in the senescence of melanocytes and nevi, we used tetracycline-based inducible expression systems in cultured melanocytic cells. We found that HDAC1 drives a sequential and cooperative activity of chromatin remodeling effectors, including transient recruitment of Brahma (Brm1) into RB/HDAC1 mega-complexes, formation of heterochromatin protein 1β (HP1β)/ SUV39H1 foci, methylation of H3-K9, stable association of RB with chromatin and significant global heterochromatinization. These chromatin changes coincide with expression of typical markers of senescence, including the senescent-associated β-galactosidase marker. Notably, formation of RB/HP1β foci and early tethering of RB to chromatin depends on intact Brm1 ATPase activity. As cells reached senescence, ejection of Brm1 from chromatin coincided with its dissociation from HP1β/RB and relocalization to protein complexes of lower molecular weight. These results provide new insights into the role of the RB pathway in regulating cellular senescence and implicate HDAC1 as a likely mediator of early chromatin remodeling events.

Original languageEnglish (US)
Pages (from-to)577-591
Number of pages15
JournalAging Cell
Volume6
Issue number4
DOIs
StatePublished - Aug 2007

Fingerprint

Pigmented Nevus
Chromatin Assembly and Disassembly
Retinoblastoma
Cell Aging
Chromatin
Growth
Melanocytes
Nevus
Intradermal Nevus
Galactosidases
Retinoblastoma Protein
Histone Deacetylases
Tetracycline
Oncogenes
Methylation
Adenosine Triphosphatases
Cultured Cells
Molecular Weight
Skin

Keywords

  • Brm1
  • HDAC1
  • Human melanocytes
  • Melanocyticnevi
  • Melanoma
  • RB

ASJC Scopus subject areas

  • Cell Biology

Cite this

Bandyopadhyay, D., Curry, J. L., Lin, Q., Richards, H. W., Chen, D., Hornsby, P. J., ... Medrano, E. E. (2007). Dynamic assembly of chromatin complexes during cellular senescence: Implications for the growth arrest of human melanocytic nevi. Aging Cell, 6(4), 577-591. https://doi.org/10.1111/j.1474-9726.2007.00308.x

Dynamic assembly of chromatin complexes during cellular senescence : Implications for the growth arrest of human melanocytic nevi. / Bandyopadhyay, Debdutta; Curry, Jonathan L.; Lin, Qiushi; Richards, Hunter W.; Chen, Dahu; Hornsby, Peter J; Timchenko, Nikolai A.; Medrano, Estela E.

In: Aging Cell, Vol. 6, No. 4, 08.2007, p. 577-591.

Research output: Contribution to journalArticle

Bandyopadhyay, D, Curry, JL, Lin, Q, Richards, HW, Chen, D, Hornsby, PJ, Timchenko, NA & Medrano, EE 2007, 'Dynamic assembly of chromatin complexes during cellular senescence: Implications for the growth arrest of human melanocytic nevi', Aging Cell, vol. 6, no. 4, pp. 577-591. https://doi.org/10.1111/j.1474-9726.2007.00308.x
Bandyopadhyay, Debdutta ; Curry, Jonathan L. ; Lin, Qiushi ; Richards, Hunter W. ; Chen, Dahu ; Hornsby, Peter J ; Timchenko, Nikolai A. ; Medrano, Estela E. / Dynamic assembly of chromatin complexes during cellular senescence : Implications for the growth arrest of human melanocytic nevi. In: Aging Cell. 2007 ; Vol. 6, No. 4. pp. 577-591.
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