Academic journal article Genetics

Replisome Function during Replicative Stress Is Modulated by Histone H3 Lysine 56 Acetylation through Ctf4

Academic journal article Genetics

Replisome Function during Replicative Stress Is Modulated by Histone H3 Lysine 56 Acetylation through Ctf4

Article excerpt

THE eukaryotic replisome consists of polymerases and an essential DNA helicase that are linked by a number of factors assembled during the initiation of chromosome replication. Progression of the replication fork depends on the activity of the replisome progression complex (RPC). This complex is uniquely present during S phase (Gambus et al. 2006) and remains associated with the replication fork until completion of DNA replication. In Saccharomyces cerevisiae,theRPCismadeupof Mcm10, Mrc1, Tof1, Csm3, Ctf4, Top1,FACT(Spt16 and Pob3), and the CMG complex comprising Cdc45,Mcm2-7 (MCM), and the go ichi ni san (GINS) complex. The CMG constitutes the core replicative helicase responsible for the movement and activities of the replication fork (Pacek et al. 2006; Bochman and Schwacha 2009).

The link between helicase and polymerases is a crucial determinant for the regulation of the replisome. The leadingstrand DNA polymerase-? was recently shown to be integrated into the replisome via an interaction with the GINS complex (Sengupta et al. 2013). Furthermore, the DNA polymerase- a-primase complex, which initiates DNA synthesis at replication origins and continues to prime Okazaki fragments at the fork, remains associated with the RPC via the Ctf4 trimer, which simultaneously interacts with the GINS complex (Gambus et al. 2009; Tanaka et al. 2009; Gosnell and Christensen 2011; Simon et al. 2014).

Cells have evolved different mechanisms to maintain genome integrity under the conditions threatening replication progression (Jossen and Bermejo 2013; Leman and Noguchi 2013). The S-phase checkpoint mediated by MRC1 was initially characterized as a pathway activated by fork stalling and able to both stabilize the replisome and delay cell cycle progression (Elledge 1996; Sancar et al. 2004; Labib and De Piccoli 2011).

It was further shown that, during DNA replication stress, lack of either MRC1 or CTF4 leads to uncoupling between the replicative polymerases and RPC, as well as a dissociation of replisome components (Bando et al. 2009; Tanaka et al. 2009; Mimura et al. 2010). Unlike MRC1, CTF4 is not required for S-phase checkpoint activation.

Ctf4 was initially identified in S. cerevisiae as a chromosome transmission fidelity factor required for the maintenance of genome stability and sister-chromatid cohesion (Spencer et al. 1990; Jawad and Paoli 2002; Gambus et al. 2006; Lengronne et al. 2006). CTF4 is not essential for budding yeast viability (Miles and Formosa 1992), but its deletion greatly sensitizes cells to DNA replication drugs (Ogiwara et al. 2007). Mechanistically, Ctf4 is required for coordination between DNA unwinding and synthesis, and it also stabilizes polymerase-a at the replication forks (Gambus et al. 2009; Tanaka et al. 2009; Mimura et al. 2010). Among various partners, Ctf4 interacts with an F-box protein Dia2 involved in the regulation of DNA replication (Mimura et al. 2009) and with Mms22,anadaptor protein of the Cul4(Ddb1)-like E3 ubiquitin ligase complex (Gambus et al. 2009; Mimura et al. 2009, 2010). The latter also includes Mms1 and cullin Rtt101,bothcrucialformaintaining replisome integrity in hydroxyurea and therefore for efficient recovery from replication stress (Luke et al. 2006; Duro et al. 2008; Zaidi et al. 2008; Gambus et al. 2009; Mimura et al. 2010; Vaisica et al. 2011).

The Rrm3 helicase travels with the replication fork and facilitates the progression of replication forks through nonhistone protein-DNA complexes throughout the genome (Azvolinsky et al. 2009; Fachinetti et al. 2010). In the absence of RRM3, chromosome breaks occur at discrete fork pause sites at specific genomic locations (Ivessa et al. 2003). A number of studies indicate that the DNA breaks generated in rrm3D cells affect cell viability in the absence of the so-called "H3K56 acetylation pathway" that comprises ASF1, RTT109, RTT101, MMS1,andMMS22 (Tong et al. 2004; Luke et al. 2006; Pan et al. 2006; Collins et al. …

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