Aging results in numerous cellular defects. damage to almost any biological

Aging results in numerous cellular defects. damage to almost any biological molecule has been implicated in aing-related deterioration it is notable that most human premature aging syndromes are caused by defects in genome surveillance indicating that DNA damage repair is usually a central pathway in aging (Freitas et al. 2011 Lombard et al. 2005 This notion is usually further supported by the fact that one of the most prominent hallmarks of aging cells is the accumulation of various types of DNA damage of which DSBs are the most deleterious (Sedelnikova et al. 2008 Sedelnikova et al. 2004 In addition to DNA damage aging brings about dramatic changes in the packaging of DNA into higher-order chromatin structure. Perhaps the most significant of these changes are the evolutionarily conserved global loss of highly condensed transcriptionally silent chromatin or heterochromatin as well as alterations in histone composition during replicative aging (Feser et al. 2010 O’Sullivan et al. 2010 Tsurumi and Li 2012 Aging-related chromatin defects are pronounced features of cells from patients with premature aging disorders but are also prominent in aging cell populations in humans worms and flies (Pegoraro et al. 2009 Scaffidi and Misteli 2006 The physiological relevance of aging-associated chromatin changes is usually most obvious in the brain where altered chromatin plasticity has been linked to transcriptional deregulation and concomitant age-related memory impairment (Peleg et al. 2010 Notably reversal of some of these changes abolishes neurodegeneration-associated memory impairments in a mouse model (Peleg et al. 2010 (Graff et al. 2012 DNA damage chromatin defects and changes in global gene expression programs associated with aging are not unrelated events (Fig. 1). We discuss here recent findings highlighting the complex interplay between DNA damage chromatin and transcription as they occur in the context of aging. Physique 1 The trinity of DNA damage chromatin and transcription in aging Chromatin context affects DNA damage signaling The sensing of DNA lesions by the DNA damage response (DDR) machinery occurs in the context of the highly complex and heterogeneous chromatin environment (Misteli and Soutoglou 2009 Shi and Sirt7 Oberdoerffer 2012 One of the classic hallmarks of the DDR is the phosphorylation of the histone variant H2AX (γ-H2AX) which is usually important for recruitment and retention of downstream DNA repair factors (Polo and Jackson 2011 γ-H2AX is usually primarily generated by the ATM kinase and subsequent transduction and amplification of the response results in the spreading of this mark to form megabase domains TAK-438 surrounding the damage site (Burma et al. 2001 Rogakou et al. 1999 Recent genome-wide profiling studies have revealed a discontinuous pattern of γ-H2AX distributing as well as its depletion from actively-transcribed genes after DNA damage TAK-438 suggesting that precisely controlled γ-H2AX propagation might safeguard the transcriptional status of genes (Iacovoni et al. 2010 Notably accumulation of γ-H2AX TAK-438 foci is usually a characteristic feature of both aged cells and cells from several premature aging disorders (Sedelnikova et al. 2008 Sedelnikova et al. 2004 and may contribute to aging-associated transcriptional deregulation. The formation of γ-H2AX domains is limited in areas with compact heterochromatin structure including senescence-associated heterochromatin foci (SAHF) (Di Micco et al. 2011 Goodarzi et al. 2010 The simplest interpretation of the reduced levels of γ-H2AX in heterochromatin is usually that damage cannot be efficiently acknowledged in heterochromatin. However this might be an oversimplification as damage is usually TAK-438 efficiently TAK-438 marked by γ-H2AX in highly-condensed mitotic chromosomes but fails to fully activate the DDR (Giunta et al. 2011 An alternative interpretation is usually that alterations in chromatin structure rather than the DSB itself may be sensed by the DNA damage machinery (Bakkenist and Kastan 2003 Bencokova et al. 2009 Hunt et al. 2007 It is thus possible that the initial signaling of DNA damage occurs within and is facilitated by chromatin structure and it is instead the amplification of γ-H2AX and the transmission of a full-scale DDR that is restrained by.

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