Ageing-related chromatin defects through loss of the NURD complex

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Abstract
Cells undergoing normal or premature ageing show several global defects in chromatin. Components of the NURD chromatin remodelling complex, such as histone chaperones, are now shown to be lost in cells from patients with a premature aging disorder and in normally aged cells. Conversely, depleting NURD subunits and Hdac1 recapitulates the chromatin defects seen in aged cells. 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.