In order to survive, cells have evolved highly effective repair mechanisms

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In order to survive, cells have evolved highly effective repair mechanisms to deal with the potentially lethal DNA damage produced by exposure to endogenous as well as exogenous agents. processes such as gene transcription or DNA replication. Similarly, during the process of DNA damage sensing and repair, chromatin needs to undergo several changes in order to facilitate accessibility of the repair machinery. Cells utilize MK-1775 pontent inhibitor several factors to modify the chromatin in order to locally open up the structure to reveal the underlying DNA sequence but post-translational modification of the histone components is one of the primary mechanisms. In this review, we will summarize chromatin modifications by the respective chromatin modifying factors that occur during the DNA damage response. male X chromosome (Turner et al., 1992) and correlated with gene dosage compensation. The modification has also been implicated in the control of chromatin structure responsible for interaction of other proteins (Shogren-Knaak et al., 2006). The acetyl-transferase responsible for histone H4 acetylation at K16 is MOF (Gupta et al., 2005, 2008; Smith et al., 2005; Sharma et al., 2010). Acetylation at H4 K16 (H4K16ac) has been MK-1775 pontent inhibitor implicated in the proper compaction of chromatin 30-nm fibers (Shogren-Knaak et al., 2006). More importantly, lack of MOF also influences ATM activation (Gupta et al., 2005) and results in delayed appearance WNT16 of IR-induced -H2AX foci (Sharma et al., 2010). Consistent with the influence of histone H4 K16 acetylation on ATM activation, HDAC inhibitor treatment results in global ATM activation even in the absence of DNA damage (Bakkenist and Kastan, 2003). Table 3 Histone acetylation. RuvABC complex and the eukaryotic Gen1 protein incise Holliday junctions producing directly ligatable crossover and non-crossover products. Alternatively, a DNA helicase, BLM, in combination with a type I topoisomerase, can resolve Holliday junctions. Branched DNA intermediates in HR can be acted upon by evolutionary-conserved structure-specific endonucleases also, including Slx1/Slx4 and Mus81/Eme1. Through the HR procedure, several acetylation events happen on histones H3 and H4 using the protein implicated in the changes becoming GCN5, NuA4, and Head wear1 (Tamburini and Tyler, 2005; Murr et al., 2006). GCN5 also takes on some part in pathway choice for DSB restoration as DNA-PKcs phosphorylates GCN5 to inactivate its Head wear domain. Furthermore, GCN5 also interacts with BRCA1 through a system that is influenced by its Head wear activity, suggesting a job in HR restoration of DNA DSBs (Oishi et al., 2006). During HR restoration, MDC1 recruits RNF8 (E3) to ubiquitinate H2AX (Kolas et al., 2007; Yaffe and Mohammad, 2009). Subsequently, recruited BRCA1 additional keeps H2AX ubiquitination to be able to recruit downstream DSB and DDR fix parts. Furthermore, in the conclusion of HR restoration chromatin structure should be restored towards the pre-damage condition, an activity that starts with dephosphorylation of -H2AX by protein phosphatase 2A (PP2A) or PP4C in mammals (Hanks et al., 1983). Removal of acetylation marks occurs by HDACs, which subsequently results in the condensation of chromatin back to its native configuration. Besides the chromatin modifying factors, MK-1775 pontent inhibitor a non-histone chromatin protein known as HP1, initially identified in and named for its predominant localization to pericentric heterochromatin (Li and Smerdon, 2002), plays a role in genomic stability (Sharma et al., 2003). There are three mammalian HP1 isoforms termed HP1, HP1 (M31) (Cbx1), and HP1 (M32) (Singh et al., 1991; Eissenberg and Elgin, 2000; Jones et al., 2000). HP1 is a dosage-dependent modifier of pericentric heterochromatin-induced silencing (Festenstein et al., 1999). HP1 plays a critical role in maintaining genomic stability in mammalian cells (Sharma et al., 2003; Aucott et al., 2008) with both negative (Ayoub et al., 2008; Goodarzi et al., 2008) as well as positive (Luijsterburg et al., 2009) effects on DNA damage repair. First, damage-dependent phosphorylation of HP1 decreases its chromodomain-dependent affinity for H3K9me3 leading to transient displacement of HP1 from DNA damage sites (Ayoub et al., 2008). In addition, HP1 depletion alleviates the ATM requirement for efficient DSB repair in heterochromatic regions (Goodarzi et al., 2008), suggesting HP1 suppresses repair in heterochromatic DNA regions. However, HP1 was also found to accumulate at DNA damage sites, indicating a more active involvement in DNA repair (Luijsterburg et al., 2009). In human cells, HP1 overexpression increased IR-induced chromosomal damage (Sharma et al., 2003). HP1 mobilization during DNA repair is regulated by ATM-dependent KAP-1 Ser473 phosphorylation (Ziv et al., 2006; Bolderson et al., 2012). CONCLUSION AND FUTURE DIRECTIONS While the mechanisms by which cells activate the DDR and repair DNA damage are becoming clear, much less is known about how.