Spreading of mammalian DNA-damage response factors studied by ChIP-chip at damaged telomeres

Meier, Andreas; Fiegler, Heike; Muñoz, Purificacı́on; Ellis, Peter; Rigler, Diane; Langford, Cordelia; Blasco, Marı́a A.; Carter, Nigel; Jackson, Stephen

doi:10.1038/sj.emboj.7601719

Cited by 88 publications

(85 citation statements)

References 53 publications

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“…It's been now well documented that the telomeres are closely linked to the DNA damage response machinery. Many DNA repair proteins such as Mre11/ Rad50/NBS, Ku, DNA PKcs, BLM/WRN and ERCC1/XPC have been found to be associated with telomeres [35][36][37]. Senescent cells exhibit distinct DNA foci at dysfunctional telomeres that contain DNA damage response proteins such as 53BP1, Rad17, H2AX, Mre11 and ATM [38][39][40][41].…”

Section: Telomerase In Dna Damage Responsesmentioning

confidence: 99%

Actions of human telomerase beyond telomeres

Cong

Shay²

2008

Cell Res

206

164

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Section: Telomerase In Dna Damage Responsesmentioning

confidence: 99%

Actions of human telomerase beyond telomeres

Cong

Shay²

2008

Cell Res

206

164

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“…In senescence cells, where telomerase activity decreases, telomeres accumulate γH2A.X foci (Meier et al, 2007). Because telomerase activity is high in germ cells, but lower in cleavage stage embryos, telomeres lengthen drastically during preimplantation development (Liu et al, 2007).…”

Section: B Cmentioning

confidence: 99%

Distribution of p53 binding protein 1 (53BP1) and phosphorylated H2A.X during mouse preimplantation development in the absence of DNA damage

Ziegler-Birling¹,

Helmrich²,

Tora³

et al. 2009

Int. J. Dev. Biol.

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The cells in the preimplantation mammalian embryo undergo several rounds of fast cell division. Whether the known DNA repair pathways are active during these early stages of development where cell division is of primary importance, has not been fully established. Because of the important role of phosphorylated H2A.X (γH2A.X) in the DNA damage response as well as its putative role in assembly of embryonic chromatin, we analysed its distribution in the preimplantation mouse embryo. We found that H2A.X is highly phosphorylated throughout preimplantation development in the absence of any induced DNA damage. Moreover, γH2A.X levels vary significantly throughout the cell cycle. Interestingly, after the 4-cell stage, we detected high levels of H2A.X phosphorylation in mitosis, where telomeres appeared focally enriched with γH2A.X. In contrast, 53BP1, which is known to be recruited to DNA damage sites, is undetectable at mitotic chromosomes at these stages and its localisation changes upon blastocyst formation from mainly nuclear to cytoplasmic. We also show that 53BP1 and γH2A.X rarely colocalise, suggesting that the high levels of phosphorylation of H2A.X in the embryo might not be directly linked to the DNA damage response in the embryo. Our data suggest that phosphorylation of H2A.X is an important event in the fast dividing cells of the early embryo in the absence of any induced DNA damage. We discuss the possible consequences of these findings on the genomewide chromatin remodelling that ocurs in the preimplantation mammalian embryo.

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“…1A,E) and months (data not shown). These IR-induced persistent DNA damage foci contained many proteins that are also present in transient foci or foci that mark dysfunctional telomeres (d'Adda di Fagagna et al, 2003;Herbig et al, 2004;Lisby et al, 2004;Meier et al, 2007;Rogakou et al, 1999;Takai et al, 2003). Such proteins included the modified chromatin component H2AX (see Fig.…”

Section: Kinetics Of Transient Versus Persistent Dna Damage Focimentioning

confidence: 99%

“…Many of these DDR signaling and repair proteins assemble rapidly (within minutes) around DSBs and can be detected in the nuclei of fixed or living cells as focal aggregates termed DNA damage foci. Two components are typically used to detect these foci by fluorescence microscopy: the PIKKphosphorylated form of the histone variant H2A.x (H2AX), and the adaptor protein tumor suppressor p53-binding protein 1 (53BP1) (Celeste et al, 2003;Huyen et al, 2004;Lobrich et al, 2010;Meier et al, 2007;Rogakou et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion

Rodier

Muñoz

Teachenor

et al. 2011

Journal of Cell Science

453

395

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SummaryDNA damage can induce a tumor suppressive response termed cellular senescence. Damaged senescent cells permanently arrest growth, secrete inflammatory cytokines and other proteins and harbor persistent nuclear foci that contain DNA damage response (DDR) proteins. To understand how persistent damage foci differ from transient foci that mark repairable DNA lesions, we identify sequential events that differentiate transient foci from persistent foci, which we term 'DNA segments with chromatin alterations reinforcing senescence' (DNA-SCARS). Unlike transient foci, DNA-SCARS associate with PML nuclear bodies, lack the DNA repair proteins RPA and RAD51, lack single-stranded DNA and DNA synthesis and accumulate activated forms of the DDR mediators CHK2 and p53. DNA-SCARS form independently of p53, pRB and several other checkpoint and repair proteins but require p53 and pRb to trigger the senescence growth arrest. Importantly, depletion of the DNA-SCARS-stabilizing component histone H2AX did not deplete 53BP1 from DNA-SCARS but diminished the presence of MDC1 and activated CHK2. Furthermore, depletion of H2AX reduced both the p53-dependent senescence growth arrest and p53-independent cytokine secretion. DNA-SCARS were also observed following severe damage to multiple human cell types and mouse tissues, suggesting that they can be used in combination with other markers to identify senescent cells. Thus, DNA-SCARS are dynamically formed distinct structures that functionally regulate multiple aspects of the senescent phenotype.

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Spreading of mammalian DNA-damage response factors studied by ChIP-chip at damaged telomeres

Cited by 88 publications

References 53 publications

Actions of human telomerase beyond telomeres

Actions of human telomerase beyond telomeres

Distribution of p53 binding protein 1 (53BP1) and phosphorylated H2A.X during mouse preimplantation development in the absence of DNA damage

DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion

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