These data indicate that epigenetic inheritance of modified Cyclopamine order histones may proceed via more than one pathway. Another example of templating comes from Drosophila, in which the centromeric histone variant CID

derived from the sperm is used to template CID deposition at the centromere during embryogenesis [ 34•]. While fertilization can occur with sperm that lack CID, the embryos do not develop normally, and paternal chromosomes lose the ability to recruit maternal CID and re-establish functional centromeres. Thus CID deposition during embryogenesis also appears to depend on a templating mechanism, although it is unclear whether it proceeds via direct or indirect recruitment. Interestingly, several epigenetic marks on the H3 histones appear to be important for proper recycling of old histones to the newly replicated DNA, and these marks have been shown to change under conditions of replication stress [ 35]. However, the mechanism by which nucleosome inheritance is regulated still remains unexplored. Investigations Crizotinib concentration into the influence of transcription rate, histone availability, and timing of replication may all provide important insights into how histones provide the genome with a molecular memory. The ability of chromatin to protect DNA from ionizing radiation was established in a seminal study over 20 years ago. When DNA was completely

stripped of its nucleosomes Loperamide and exposed to 20 Gy of gamma-radiation, the occurrence of double strand breaks (DSBs) was 10 times greater than that of intact cells [36]. However the discovery that histone variants are intimately tied to proper DNA damage response (DDR) progression is relatively recent. In particular, work has focused on the role played by variants of the H2A family: (γ)H2A.X, H2A.Z and macroH2A. While the localized phosphorylation of H2A.X has been

implicated in the response to DSBs for some time, it is only recently that the behavior of H2A.X in response to clustered DNA lesions has been elucidated. Interestingly, when clustered DSBs were induced by ionizing radiation in skin fibroblasts, H2A.X phosphorylation, monitored by immunostaining, was not limited to the region directly surrounding the break, but occurred throughout the genome in a dose dependent manner [37]. This response, catalyzed by two kinases, ATM and DNA-PK, was transient and not linked to apoptosis. Recently, using ChIP at a defined DSB, a second H2A variant usually involved in transcriptional regulation, H2A.Z, was found at the break site [38]. H2A.Z is deposited at the DSB by the ATP-dependent chromatin remodeler p400, and is thought to re-organize the chromatin surrounding the DSB into a more fluid conformation by promoting H4 acetylation (Figure 3).