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Vol. 16, Issue 10, 5013-5025, October 2005
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Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Alberta T6G 1Z2, Canada
Submitted January 24, 2005;
Revised June 13, 2005;
Accepted July 8, 2005
Monitoring Editor: Kerry Bloom
H2AX is a core histone H2A variant that contains an absolutely conserved serine/glutamine (SQ) motif within an extended carboxy-terminal tail. H2AX phosphorylation at the SQ motif (
-H2AX) has been shown to increase dramatically upon exogenously introduced DNA double-strand breaks (DSBs). In this study, we use quantitative in situ approaches to investigate the spatial patterning and cell cycle dynamics of -H2AX in a panel of normally growing (unirradiated) mammalian cell lines and cultures. We provide the first evidence for the existence of two distinct yet highly discernible -H2AX focal populations: a small population of large amorphous foci that colocalize with numerous DNA DSB repair proteins and previously undescribed but much more abundant small foci. These small foci do not recruit proteins involved in DNA DSB repair. Cell cycle analyses reveal unexpected dynamics for -H2AX in unirradiated mammalian cells that include an ATM-dependent phosphorylation that is maximal during M phase. Based upon similarities drawn from other histone posttranslational modifications and previous observations in haploinsufficient (H2AX-/+) and null mice (H2AX-/-), -H2AX may contribute to the fidelity of the mitotic process, even in the absence of DNA damage, thereby ensuring the faithful transmission of genetic information from one generation to the next.
Abbreviations used: ATM, ataxia telangiectasia mutated; DNA DSB, DNA double-strand break; DIM, digital imaging microscopy; DNA-PKCS, DNA protein kinase, catalytic subunit; M, metaphase; P/PM, prophase/prometaphase; QIM, quantitative imaging microscopy.
The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).
Address correspondence to: Michael J. Hendzel (michaelh{at}cancerboard.ab.ca).
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