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Published 9 October 2006. doi:10.1083/jcb.200604009
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 175, Number 1, 55-66
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Article

Promyelocytic leukemia nuclear bodies behave as DNA damage sensors whose response to DNA double-strand breaks is regulated by NBS1 and the kinases ATM, Chk2, and ATR



Graham Dellaire1,2, Reagan W. Ching1, Kashif Ahmed1, Farid Jalali3, Kenneth C.K. Tse3, Robert G. Bristow3,4,5, and David P. Bazett-Jones1

1 The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
2 Department of Pathology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada
3 Ontario Cancer Institute/Princess Margaret Hospital, University Health Network, 4 Department of Radiation Oncology, and 5 Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 3G4, Canada

Correspondence to David P. Bazett-Jones: dbjones{at}sickkids.ca

The promyelocytic leukemia (PML) nuclear body (NB) is a dynamic subnuclear compartment that is implicated in tumor suppression, as well as in the transcription, replication, and repair of DNA. PML NB number can change during the cell cycle, increasing in S phase and in response to cellular stress, including DNA damage. Although topological changes in chromatin after DNA damage may affect the integrity of PML NBs, the molecular or structural basis for an increase in PML NB number has not been elucidated. We demonstrate that after DNA double-strand break induction, the increase in PML NB number is based on a biophysical process, as well as ongoing cell cycle progression and DNA repair. PML NBs increase in number by a supramolecular fission mechanism similar to that observed in S-phase cells, and which is delayed or inhibited by the loss of function of NBS1, ATM, Chk2, and ATR kinase. Therefore, an increase in PML NB number is an intrinsic element of the cellular response to DNA damage.

Abbreviations used in this paper: ANOVA, analysis of variance; AT, ataxia telangiectasia; ATLD, AT-like disorder; ATM, ataxia telangiectasia mutated; ATR, AT and Rad3-related; DSB, double-strand break; ESI, electron spectroscopic imaging; Gy, Gray; GFP, green fluorescent protein; ICD, interchromatin domain; IF, immunofluorescence; IR, ionizing radiation; LM, light microscopy; LSM, laser scanning confocal microscopy; MEF, murine embryonic fibroblast; MRN, Mre11–Rad50–Nbs1; NB, nuclear body; NBS, Nijmegen breakage syndrome; NHDF, normal human diploid fibroblasts; PK, protein kinase; PML, promyelocytic leukemia; ROI, region if interest; RPA, replication protein A; SUMO, small ubiquitin-like modifier.


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