Evidence for the receipt of DNA damage stimuli by PML nuclear domains

A. Varadaraj, C. L. Dovey, L. Laredj, B. Ferguson, C. E. Alexander, N. Lubben, A. H. Wylie, T. Rich

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Promyelocytic leukaemia nuclear domains (PML-NDs) comprise a shell of PML protein and many labile cargo proteins. The nature of their cargo, their juxtaposition to foci of damaged DNA following ionizing radiation (IR), and the altered DNA damage responses in PML null cells all implicate PML-NDs in the DNA damage response. In this work, the propensity of PML-NDs to increase in number and decrease in size following IR has been studied. Serial quantitative studies of endogenous PML-NDs prove that the PML-ND response to IR is not the result of the asymmetry in cell cycle distribution that can follow IR, but reflects more directly the process of DNA damage. The response is swift, sensitive (evident after 1 Gy), and potentially reversible in untransformed fibroblasts. In these cells and in HCT116 colon cancer cells, failure to restore PML-ND number within 24 h correlates with later loss of growth potential - in fibroblasts, through prolonged cell cycle arrest and in HCT116 cells, through apoptosis. Failure to express an intact ATM/CHK2 DNA damage signalling pathway in either cell type leads to a delay in the PML-ND response to IR. Conversely, cell cycle progression following IR in cells that detect damaged DNA accelerates PML-ND reorganization. Collectively, these data show that the increase in PML-ND number seen after irradiation is, in part, triggered by the receipt of the DNA damage stimulus. The senescent cell state is also associated with chronic DNA damage and Hayflick-limited fibroblasts were found to express nuclei with elevated numbers of PML-NDs before IR that remained unresponsive to IR. Though the underlying reasons for damage-induced PML alteration remain obscure, it is noteworthy that significant numbers of PML-NDs juxtapose with ionizing radiation-induced foci after IR. The co-regulation of these structures may necessitate the stereotyped increases in PML-ND number following damage.

Original languageEnglish
Pages (from-to)471-480
Number of pages10
JournalJournal of Pathology
Volume211
Issue number4
DOIs
Publication statusPublished - Mar 2007

Fingerprint

DNA Damage
Ionizing Radiation
Leukemia
HCT116 Cells
Fibroblasts
Cell Cycle
Null Lymphocytes
DNA
Cell Cycle Checkpoints
Colonic Neoplasms
Proteins
Apoptosis

Keywords

  • CHK2
  • DNA damage
  • HCT116
  • IRIF
  • PML

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Varadaraj, A., Dovey, C. L., Laredj, L., Ferguson, B., Alexander, C. E., Lubben, N., ... Rich, T. (2007). Evidence for the receipt of DNA damage stimuli by PML nuclear domains. Journal of Pathology, 211(4), 471-480. https://doi.org/10.1002/path.2126

Evidence for the receipt of DNA damage stimuli by PML nuclear domains. / Varadaraj, A.; Dovey, C. L.; Laredj, L.; Ferguson, B.; Alexander, C. E.; Lubben, N.; Wylie, A. H.; Rich, T.

In: Journal of Pathology, Vol. 211, No. 4, 03.2007, p. 471-480.

Research output: Contribution to journalArticle

Varadaraj, A, Dovey, CL, Laredj, L, Ferguson, B, Alexander, CE, Lubben, N, Wylie, AH & Rich, T 2007, 'Evidence for the receipt of DNA damage stimuli by PML nuclear domains', Journal of Pathology, vol. 211, no. 4, pp. 471-480. https://doi.org/10.1002/path.2126
Varadaraj A, Dovey CL, Laredj L, Ferguson B, Alexander CE, Lubben N et al. Evidence for the receipt of DNA damage stimuli by PML nuclear domains. Journal of Pathology. 2007 Mar;211(4):471-480. https://doi.org/10.1002/path.2126
Varadaraj, A. ; Dovey, C. L. ; Laredj, L. ; Ferguson, B. ; Alexander, C. E. ; Lubben, N. ; Wylie, A. H. ; Rich, T. / Evidence for the receipt of DNA damage stimuli by PML nuclear domains. In: Journal of Pathology. 2007 ; Vol. 211, No. 4. pp. 471-480.
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