Budding yeast Mms22 and Mms1 regulate homologous recombination induced by replisome blockage

Duro, Eris; Vaisica, Jessica A.; Brown, Grant W.; Rouse, John

doi:10.1016/j.dnarep.2008.01.007

Cited by 60 publications

(93 citation statements)

References 30 publications

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“…In the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, newly synthesized histone H3 molecules are abundantly acetylated on lysine 56 (5)(6)(7). In S. cerevisiae, H3K56 acetylation is required for replication fork stability (8,9), reassembly of chromatin after DNA damage repair, and histone association with chromatin assembly proteins (10)(11)(12)(13). A fungalspecific histone acetyl-transferase (HAT) enzyme, termed Rtt109, and its stimulatory histone chaperone cofactor, Asf1, are required for H3K56 acetylation (8,(14)(15)(16).…”

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Histone acetyltransferase Rtt109 is required for Candida albicans pathogenesis

Rosa

Boyartchuk

Zhu

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

125

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Candida albicans is a ubiquitous opportunistic pathogen that is the most prevalent cause of hospital-acquired fungal infections. In mammalian hosts, C. albicans is engulfed by phagocytes that attack the pathogen with DNA-damaging reactive oxygen species (ROS). Acetylation of histone H3 lysine 56 (H3K56) by the fungal-specific histone acetyltransferase Rtt109 is important for yeast model organisms to survive DNA damage and maintain genome integrity. To assess the importance of Rtt109 for C. albicans pathogenicity, we deleted the predicted homolog of Rtt109 in the clinical C. albicans isolate, SC5314. C. albicans rtt109 −/− mutant cells lack acetylated H3K56 (H3K56ac) and are hypersensitive to genotoxic agents. Additionally, rtt109 −/− mutant cells constitutively display increased H2A S129 phosphorylation and elevated DNA repair gene expression, consistent with endogenous DNA damage. Importantly, C. albicans rtt109 −/− cells are significantly less pathogenic in mice and more susceptible to killing by macrophages in vitro than are wild-type cells. Via pharmacological inhibition of the host NADPH oxidase enzyme, we show that the increased sensitivity of rtt109 −/− cells to macrophages depends on the host's ability to generate ROS, providing a mechanistic link between the drug sensitivity, gene expression, and pathogenesis phenotypes. We conclude that Rtt109 is particularly important for fungal pathogenicity, suggesting a unique target for therapeutic antifungal compounds.acetylation | chromatin | fungal pathogenesis | DNA damage resistance | macrophage

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confidence: 99%

Histone acetyltransferase Rtt109 is required for Candida albicans pathogenesis

Rosa

Boyartchuk

Zhu

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

125

127

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“…97 Indeed, removing Rtt109 or the Rtt101 complex impairs recombinational repair and replication, and sensitizes cells to replication stress. 93,94,[98][99][100][101] Once replication is completed, histone deacetylases Hst3 and Hst4 remove the acetyl group from H3K56ac to establish a more stable nucleosome state. [102][103][104] Cells lacking Hst3 and Hst4 or containing the acetylation mimetic H3 mutation (H3K56Q) exhibit defects such as persistent checkpoint and sensitivity to higher temperature and genotoxins.…”

Section: Roles Of Rtt107 When Partnered With Rtt101 Cullin Ubiquitin mentioning

confidence: 99%

Multi-BRCT scaffolds use distinct strategies to support genome maintenance

2016

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Genome maintenance requires coordinated actions of diverse DNA metabolism processes. Scaffolding proteins, such as those containing multiple BRCT domains, can influence these processes by collaborating with numerous partners. The best-studied examples of multi-BRCT scaffolds are the budding yeast Dpb11 and its homologues in other organisms, which regulate DNA replication, repair, and damage checkpoints. Recent studies have shed light on another group of multi-BRCT scaffolds, including Rtt107 in budding yeast and related proteins in other organisms. These proteins also influence several DNA metabolism pathways, though they use strategies unlike those employed by the Dpb11 family of proteins. Yet, at the same time, these 2 classes of multi-BRCT proteins can collaborate under specific situations. This review summarizes recent advances in our understanding of how these multi-BRCT proteins function in distinct manners and how they collaborate, with a focus on Dpb11 and Rtt107.

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“…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, and MMS22 (Tong et al 2004;Luke et al 2006;Pan et al 2006;Collins et al 2007;Duro et al 2008;Roberts et al 2008;Zaidi et al 2008;Costanzo et al 2010;Koh et al 2010;Mimura et al 2010).In S. cerevisiae, H3K56 localizes at the DNA entry and exit points of a nucleosome (Masumoto et al 2005;Ozdemir et al 2005;Xu et al 2005). H3K56 is transiently acetylated during the S phase of the cell cycle and after DNA damage and is rapidly de-acetylated by the action of the sirtuins Hst3 and Hst4, when cells enter the transition between G2 and M phases and after DNA repair (Masumoto et al 2005;Xu et al 2005).…”

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confidence: 99%

“…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, an adaptor protein of the Cul4(Ddb1)-like E3 ubiquitin ligase complex (Gambus et al 2009;Mimura et al 2009Mimura et al , 2010. The latter also includes Mms1 and cullin Rtt101, both crucial for maintaining 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).…”

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Replisome Function During Replicative Stress Is Modulated by Histone H3 Lysine 56 Acetylation Through Ctf4

et al. 2015

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Histone H3 lysine 56 acetylation in Saccharomyces cerevisiae is required for the maintenance of genome stability under normal conditions and upon DNA replication stress. Here we show that in the absence of H3 lysine 56 acetylation replisome components become deleterious when replication forks collapse at natural replication block sites. This lethality is not a direct consequence of chromatin assembly defects during replication fork progression. Rather, our genetic analyses suggest that in the presence of replicative stress H3 lysine 56 acetylation uncouples the Cdc45-Mcm2-7-GINS DNA helicase complex and DNA polymerases through the replisome component Ctf4. In addition, we discovered that the N-terminal domain of Ctf4, necessary for the interaction of Ctf4 with Mms22, an adaptor protein of the Rtt101-Mms1 E3 ubiquitin ligase, is required for the function of the H3 lysine 56 acetylation pathway, suggesting that replicative stress promotes the interaction between Ctf4 and Mms22. Taken together, our results indicate that Ctf4 is an essential member of the H3 lysine 56 acetylation pathway and provide novel mechanistic insights into understanding the role of H3 lysine 56 acetylation in maintaining genome stability upon replication stress. KEYWORDS Ctf4; H3K56 acetylation; Mms22; replicative stress; replisome T HE 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, the RPC is made up of Mcm10, Mrc1, Tof1, Csm3, Ctf4, Top1, FACT (Spt16 and Pob3), and the CMG complex comprising Cdc45, , 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-ɛ was recently shown to be integrated into the replisome via an interaction with the GINS complex (Sengupta et al. 2013). Furthermore, the DNA polymerasea-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 dela...

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Budding yeast Mms22 and Mms1 regulate homologous recombination induced by replisome blockage

Cited by 60 publications

References 30 publications

Histone acetyltransferase Rtt109 is required for Candida albicans pathogenesis

Histone acetyltransferase Rtt109 is required for Candida albicans pathogenesis

Multi-BRCT scaffolds use distinct strategies to support genome maintenance

Replisome Function During Replicative Stress Is Modulated by Histone H3 Lysine 56 Acetylation Through Ctf4

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