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. 2011 Apr 15;10(8):1215-21.
doi: 10.4161/cc.10.8.15334. Epub 2011 Apr 15.

Give me a break, but not in mitosis: the mitotic DNA damage response marks DNA double-strand breaks with early signaling events

Simona Giunta  1 , Stephen P Jackson
Affiliations

Give me a break, but not in mitosis: the mitotic DNA damage response marks DNA double-strand breaks with early signaling events

Simona Giunta et al. Cell Cycle. .

Abstract

: DNA double-strand breaks (DSBs) are extremely cytotoxic with a single unrepaired DSB being sufficient to induce cell death. A complex signalling cascade, termed the DNA damage response (DDR), is in place to deal with such DNA lesions and maintain genome stability. Recent work by us and others has found that the signalling cascade activated by DSBs in mitosis is truncated, displaying apical, but not downstream, components of the DDR. The E3 Ubiquitin ligases RNF8, RNF168 and BRCA1, along with the DDR mediator 53BP1, are not recruited to DSB sites in mitosis, and activation of downstream checkpoint kinases is also impaired. Here, we show that RNF8 and RNF168 are recruited to DNA damage foci in late mitosis, presumably to prime sites for 53BP1 recruitment in early G1. Interestingly, we show that, although RNF8, RNF168 and 53BP1 are excluded from DSB sites during most of mitosis, they associate with mitotic structures such as the kinetochore, suggesting roles for these DDR factors during mitotic cell division. We discuss these and other recent findings and suggest how these novel data collectively contribute to our understanding of mitosis and how cells deal with DNA damage during this crucial cell cycle stage.

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Figures

Figure 1
Figure 1
Analysis of U2OS cells stably expressing GFP-RNF8 and GFP-RNF168 show that these proteins are excluded from IRIF in early and mid-mitosis and re-associate with IRIF in late mitosis, prior to 53BP1 recruitment. (A) GFP-RNF8 forms bright dots, localizing to centrosomes in mitosis. In telophase, GFP-RNF8 starts to form IRIF and co-localizes with γH2AX. (B) GFP-RNF168 is largely excluded from chromosomes and IRIF until late mitosis, when it co-localizes with γH2AX foci. A fine GFP-RNF168 staining localized in punctate dots can be observed in mitosis, reminiscent of kinetochores. These dots do not co-localize with γH2AX. At the right are zoomed-in views of white boxes shown on the main parts. (C) Association of RNF8 with IRIF in late mitosis does not trigger recruitment of 53BP1 until cells re-enter G1. White arrows point to mitotic cells. Scale bars 10 µm.
Figure 1
Figure 1
Analysis of U2OS cells stably expressing GFP-RNF8 and GFP-RNF168 show that these proteins are excluded from IRIF in early and mid-mitosis and re-associate with IRIF in late mitosis, prior to 53BP1 recruitment. (A) GFP-RNF8 forms bright dots, localizing to centrosomes in mitosis. In telophase, GFP-RNF8 starts to form IRIF and co-localizes with γH2AX. (B) GFP-RNF168 is largely excluded from chromosomes and IRIF until late mitosis, when it co-localizes with γH2AX foci. A fine GFP-RNF168 staining localized in punctate dots can be observed in mitosis, reminiscent of kinetochores. These dots do not co-localize with γH2AX. At the right are zoomed-in views of white boxes shown on the main parts. (C) Association of RNF8 with IRIF in late mitosis does not trigger recruitment of 53BP1 until cells re-enter G1. White arrows point to mitotic cells. Scale bars 10 µm.
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