Mobilization and recruitment of HP1: A bimodal response to DNA breakage

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Abstract

The pathways that signal double-strand DNA breaks (DSBs) in mammalian cells are central to the maintenance of genome integrity. We have reported (Ayoub et al. Nature 2008; 453:682-6) that the rapid mobilization of the heterochromatin protein, HP1β, within seconds from DSB sites promotes chromatin changes like H2AX phosphorylation that trigger this response. Notably, this paper and a subsequent report (Ayoub et al. Cell Cycle 2009; 8:1494-500), demonstrate that transient HP1β mobilization is followed by its accumulation over time at DSB sites. Indeed, two recent papers (Luijsterburg et al. J Cell Biol 2009; 185:577-86 and Zarebski et al. Cytometry a 2009) suggest that HP1 recruitment to damage sites, rather than its rapid mobilization, is the predominant behavior exhibited by this protein. Here, we present new experimental analyses which corroborate that fluorophore-tagged HP1β exhibits two distinct behaviors at DSB sites in living cells - rapid, transient mobilization, most evident in heterochromatic regions, followed by slower recruitment. Experimental methods allowing visualization of these behaviors are described. Interestingly, chemical inhibition of the DNA-damage responsive enzyme, casein kinase 2 (CK2), suppresses HP1β mobilization while permitting recruitment. Our findings reconcile recent findings in a new model, wherein rapid HP1β mobilization from DSBs mediated by its phosphorylation on Thr51 by CK2, is followed by, and may overlap with, its accumulation at these sites via the chromoshadow domain, independent of Thr51. Our analyses provide fresh insight into the earliest events that trigger the DNA damage response in mammalian cells. © 2009 Landes Bioscience.

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Ayoub, N., Jeyasekharan, A. D., & Venkitaraman, A. R. (2009). Mobilization and recruitment of HP1: A bimodal response to DNA breakage. Cell Cycle, 8(18), 2946–2951. https://doi.org/10.4161/cc.8.18.9486

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