Sirtuins at the Breaking Point: SIRT6 in DNA Repair
نویسنده
چکیده
is the accumulation of unrepaired damage to cellular and organismal components over time. Damage to nuclear DNA likely contributes to the degenerative effects of aging; unlike other cellular constituents, nuclear DNA cannot be replaced [1]. A wide spectrum of DNA lesions and associated repair pathways exist [1]: non-helix distorting lesions, such as those induced by oxidative damage, are repaired via base excision repair (BER); whereas helix-distorting base changes, like those caused by UV, are fixed via nucleotide excision repair (NER) and its subpathways. DNA double strand breaks (DSBs) represent a particularly severe challenge to the cell; if left unrepaired these lesions can induce cell death, replicative senescence, or conversely promote oncogenic transformation. For this reason, cells have evolved multiple pathways to repair DSBs: classical non-homologous end-joining (C-NHEJ), homologous recombination (HR), and other pathways such as alternative NHEJ [2, 3, 4]. In this issue of Aging, work by Chua, McCord et al. suggests that SIRT6, a member of a protein family previously implicated in promoting longevity, may function at least in part via increasing efficacy of DNA repair. In eukaryotic cells, DNA does not exist as a naked double-stranded molecule; rather it is packaged with histones and other proteins into a complex structure called chromatin [5]. Transcription, replication, and repair factors must navigate this environment to interact with DNA. Covalent modification of N-terminal histone tails (via phosphorylation, methylation, ubiquitination, sumoylation, ADP-ribosylation, and acetylation) leads to alterations in chromatin function. Chromatin itself may serve as a target of age-related change; significant alterations in chromatin structure occur during senes-This is an open‐access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited cence of mammalian cells in vitro, and perhaps in the context of the whole organism as well [5]. One consequence of accumulated DNA damage and/or chromatin aberrations seems to be age-related perturb-bations in gene expression in some tissues [5, 6, 7], which may in turn lead to progressive loss of cellular and organismal homeostasis. However, these trans-criptional changes are not found in all cell types [8], implying that different tissues vary with respect to their maintenance of an appropriate gene expression pattern, and potentially chromatin structure, with age. In budding yeast and higher organisms, homologs of the Sir2 protein (the sirtuins) link chromatin structure with lifespan [9, 10]. In yeast, transcription and …
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عنوان ژورنال:
دوره 1 شماره
صفحات -
تاریخ انتشار 2009