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Ageing-related chromatin defects through loss of the NURD complex

Abstract

Physiological and premature ageing are characterized by multiple defects in chromatin structure and accumulation of persistent DNA damage. Here we identify the NURD chromatin remodelling complex as a key modulator of these ageing-associated chromatin defects. We demonstrate loss of several NURD components during premature and normal ageing and we find an ageing-associated reduction in HDAC1 activity. Silencing of individual NURD subunits recapitulated chromatin defects associated with ageing and we provide evidence that structural chromatin defects precede DNA damage accumulation. These results outline a molecular mechanism for chromatin defects during ageing.

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Figure 1: Loss of RBBP4 and RBBP7 in progerin expressing cells.
Figure 2: Heterochromatin defects and increased DNA damage on RBBP4 and RBBP7 silencing.
Figure 3: Loss of NURD subunits in HGPS cells.
Figure 4: Heterochromatin defects and increased DNA damage on silencing of NURD subunits.
Figure 5: Loss of NURD subunits in physiological ageing.

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Acknowledgements

We thank P. Scaffidi and A. Marcello for critical reading of the manuscript, and P. Scaffidi for sharing data and providing numerous suggestions during the course of the experiments. Fluorescence imaging was performed with the assistance of T. Karpova at the NCI Fluorescence Imaging Microscopy Facility. FACS cell cycle acquisition and analysis was performed with the help of K. McKinnon at the NCI FACS facility. We also thank T. Jenuwein, B. Stillman and T. Dittmer for providing reagents. We thank H. Herrmann and E. Wanker for their support with the Y2H screening and subsequent confirmation studies. G.P. was partly supported by postdoctoral fellowships from the Telethon Italy Foundation and the Italian Association for Cancer Research (AIRC). K.H. and H.G. were supported by The Deutsche Forschungsgemeinschaft (DFG, SFB 577, projects A4 and Z2). This work was supported by an Intramural Research Program of the NIH, NCI, Center for Cancer Research.

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N.K. generated the U2OS-One Strep-Lamin A cell line and optimized the biotin pulldown. U.W., H.K. and K.F. designed, performed and analysed the yeast two-hybrid experiment. G.P. performed all other experiments. G.P. and T.M. designed and analysed all experiments and wrote the manuscript.

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Correspondence to Tom Misteli.

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Pegoraro, G., Kubben, N., Wickert, U. et al. Ageing-related chromatin defects through loss of the NURD complex. Nat Cell Biol 11, 1261–1267 (2009). https://doi.org/10.1038/ncb1971

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