TY - JOUR
T1 - ssDNA fragments induce cell senescence by telomere uncapping
AU - Tsolou, Avgi
AU - Passos, João F.
AU - Nelson, Glyn
AU - Arai, Yasumichi
AU - Zglinicki, Thomas von
N1 - Funding Information:
The work was supported by a Newcastle University studentship to AT and by grants from Research into Ageing and BBSRC (CISBAN) to TvZ.
PY - 2008/10
Y1 - 2008/10
N2 - Telomere uncapping is known to induce senescence by activating a DNA damage response (DDR). However, it is still unclear what structural features of uncapped telomeres activate DDR. One hypothesis is that the exposure of the telomeric single-stranded G-rich 3′ overhang triggers a DNA damage response and is, thus, equivalent to telomere uncapping. To mimic this, we compared the effects of two short single-stranded oligonucleotides, (TTAGGG)2 and (CCCTAA)2. G-rich oligonucleotides induced DNA damage foci containing γH2AX and senescence-like arrest, whilst C-rich oligonucleotides had no effect. Oligonucleotides did not co-localize with γΗ2ΑX foci, instead the induced DNA damage foci were preferentially localized at telomeres. BrdU incorporation assays showed that the effect of G oligonucleotides on γH2AX foci formation was cell cycle-dependent; entry of cells into S phase was necessary for subsequent DNA damage foci formation. Together, our results show that short G-rich single-stranded oligonucleotides induce telomere uncapping in a cell cycle-dependent manner, probably by titrating essential factors like Pot1 away from telomeres.
AB - Telomere uncapping is known to induce senescence by activating a DNA damage response (DDR). However, it is still unclear what structural features of uncapped telomeres activate DDR. One hypothesis is that the exposure of the telomeric single-stranded G-rich 3′ overhang triggers a DNA damage response and is, thus, equivalent to telomere uncapping. To mimic this, we compared the effects of two short single-stranded oligonucleotides, (TTAGGG)2 and (CCCTAA)2. G-rich oligonucleotides induced DNA damage foci containing γH2AX and senescence-like arrest, whilst C-rich oligonucleotides had no effect. Oligonucleotides did not co-localize with γΗ2ΑX foci, instead the induced DNA damage foci were preferentially localized at telomeres. BrdU incorporation assays showed that the effect of G oligonucleotides on γH2AX foci formation was cell cycle-dependent; entry of cells into S phase was necessary for subsequent DNA damage foci formation. Together, our results show that short G-rich single-stranded oligonucleotides induce telomere uncapping in a cell cycle-dependent manner, probably by titrating essential factors like Pot1 away from telomeres.
KW - DNA damage response
KW - Oligonucleotides
KW - Senescence
KW - Telomere uncapping
KW - Telomeres
KW - ssDNA
UR - http://www.scopus.com/inward/record.url?scp=53049087243&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=53049087243&partnerID=8YFLogxK
U2 - 10.1016/j.exger.2008.08.043
DO - 10.1016/j.exger.2008.08.043
M3 - Article
C2 - 18778766
AN - SCOPUS:53049087243
VL - 43
SP - 892
EP - 899
JO - Experimental Gerontology
JF - Experimental Gerontology
SN - 0531-5565
IS - 10
ER -