Academic journal article Genetics

A Novel Histone Crosstalk Pathway Important for Regulation of UV-Induced DNA Damage Repair in Saccharomyces Cerevisiae

Academic journal article Genetics

A Novel Histone Crosstalk Pathway Important for Regulation of UV-Induced DNA Damage Repair in Saccharomyces Cerevisiae

Article excerpt

CELL survival depends on the preservation of genomic integrity. Cells are perpetually exposed to intrinsic and extrinsic factors that chemically alter DNA, potentially causing genomic instability. One of the most prevalent environmental factors that challenge genome integrity is solar radiation, specifically wavelengths that fall within the ultraviolet (UV) spectrum (Rastogi et al 2010). DNA absorbs UV radiation, leading to the formation of structurally deforming cyclo-butane pyrimidine dimers and 6-4 photoproducts. Such lesions can inhibit essential cellular operations, such as DNA replication and transcription, and can cause mutations. As a result, UV exposure is one of the greatest risk factors for environmentally associated cancer in humans (Friedberg et al. 2006).

UV-induced DNA damage is processed by a variety of molecular pathways. Initially, DNA-binding factors detect UV-induced DNA irregularities and activate cell cycle checkpoints at G1/S, mid-S, and G2/M (Sugasawa 2016). Nucleotide excision repair is the primary mechanism for repair of UV damage, in which the lesion is removed and replaced by nascent DNA (Prakash and Prakash 2000). Damage tolerance pathways also contribute to survival following UV exposure (Boiteux and Jinks-Robertson 2013). For example, "postreplication repair' describes a variety of processes that complete gaps in DNA that arise during replication of the damaged template, such as translesion synthesis (TLS), by low-fidelity DNA polymerases (Broomfield et al 2001). Likewise, recombination mechanisms can be employed to fill replicationassociated gaps via sister chromatid exchange, as well as to repair double-stranded breaks generated by UV damage (Kadyk and Hartwell 1993; Kupiec 2000; Gangavarapu et al 2007).

In eukaryotic organisms, the recognition and repair of DNA damage occurs in the context of chromatin. Minimally, chromatin must be remodeled to accommodate the repair machinery, with an "access-repair-restore" model describing the changes to chromatin that are required for efficient repair (Polo and Almouzni 2015). Consequently, chromatin-associated proteins, particularly histones, are integral players in DNA repair mechanisms. Histones are subject to a wide array of post-translational modifications, many of which have been implicated in DNA repair (Cao et al 2016). The roles of these modifications in repair include influence on DNA accessibility, recruitment of repair factors, establishment of interactions between homologous chromosomes and sister chromatids, regulation of repair-related gene expression, and modulation of cell cycle progression. Disruption of histone modifications causes various repair deficiencies, often leading to genomic instability, and, as a result, having important implications for cancer progression (Wang et al 2016).

Methylation of histone H3 at lysine 79 (H3K79me) is important for UV repair, as loss of this modification causes a reduction in survival following UV exposure (Bostelman et al. 2007; Evans et al. 2008; Chaudhuri et al. 2009). Prior studies have implicated functions for H3K79me in DNA damage checkpoint activation and global NER (Giannattasio et al. 2005; Wysocki et al. 2005; Chaudhuri et al. 2009; Tatum and Li 2011; Rossodivita et al. 2014), as well as UV-induced sister chromatid exchange (Rossodivita et al. 2014). Furthermore, we have previously reported evidence indicating that specific H3K79 methylation states play distinct roles in UV repair in yeast. H3K79 can possess up to three methyl groups per residue (denoted H3K79me1, me2, and me3), catalyzed by histone methyltransferase Dot1 (Ng et al. 2002a; van Leeuwen et al. 2002), and further influenced via crosstalk with histone H2B K123 ubiquitylation (Ng et al. 2002b; Sun and Allis 2002; Shahbazian et al. 2005; Frederiks et al. 2008). Our prior studies revealed that while both the me2 and me3 states contribute to UV-induced checkpoint activation, the me3 state is uniquely required for sister chromatid exchange in response to UV exposure (Rossodivita et al. …

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