Mms1 and Mms22 stabilize the replisome during replication stress

Vaisica, Jessica A.; Baryshnikova, Anastasija; Costanzo, Michael; Boone, Charles; Brown, Grant W.

doi:10.1091/mbc.e10-10-0848

Cited by 20 publications

(29 citation statements)

References 76 publications

(156 reference statements)

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“…This hypothesis is clearly reinforced by our findings showing that RRM3 deletion leads to an increased enrichment of Mms22. In good agreement with the fact that Mms22 is recruited to chromatin in a DNA damage-, RTT109-, and RTT101-dependent manner (Dovey et al 2009; Ben-Aroya et al 2010;Vaisica et al 2011) and, in the light of recent work showing that the Rtt101-Mms1-Mms22 complex binds H3K56ac-H4 preferentially over unmodified H3-H4 (Han et al 2013), we foresee that H3K56ac signals DNA damage and directly recruits the Rtt101-Mms1-Mms22 complex behind the fork to ubiquitylate H3K56 acetylated histones, Ctf4, and various substrates leading to an increased DNA accessibility at damage sites and improved DNA repair. Alternatively, Ctf4 could also recruit the Rtt101-Mms1 at the DNA damage fork through its interaction with Mms22, and its function at the replisome could be subsequently regulated by the complex.…”

Section: Discussionsupporting

confidence: 71%

“…Finally, our data strongly suggest that this effect is dependent upon an interaction between Ctf4 and Mms22. Similarly to ctf4D, deletion of MRC1 induces uncoupling between helicase and polymerase (Tanaka et al 2009;Mimura et al 2010;Vaisica et al 2011). In accord with this notion, we found that the replication function of MRC1 is also strongly deleterious for cells experiencing constitutive replicative damages in the absence of a functional H3K56ac pathway.…”

supporting

confidence: 78%

“…Mms22 is recruited to chromatin at stalled replication forks (Dovey et al 2009;Ben-Aroya et al 2010;Vaisica et al 2011). An attractive hypothesis would be that Ctf4 is a substrate of the Rtt101-Mms1-Mms22 complex and is further degraded at stalled replication forks under replicative stress.…”

Section: Discussionmentioning

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).…”

mentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 71%

supporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…Fork stabilization could therefore be a conserved feature of DNA-strand-exchange enzymes. There are also multiple mechanisms to stabilize blocked replication forks in eukaryotes that do not require recombination enzymes (Lopes et al 2001;Tercero and Diffley 2001;Katou et al 2003;Szyjka et al 2005;Tittel-Elmer et al 2009;Vaisica et al 2011). Perhaps the increased numbers of forks in eukaryotes demands a reduced probability of individual blocked fork instability, requiring multiple stabilization mechanisms.…”

Section: Fork Stabilitymentioning

confidence: 99%

Recombination and Replication

Syeda

Hawkins

McGlynn

2014

Cold Spring Harbor Perspectives in Biology

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The links between recombination and replication have been appreciated for decades and it is now generally accepted that these two fundamental aspects of DNA metabolism are inseparable: Homologous recombination is essential for completion of DNA replication and vice versa. This review focuses on the roles that recombination enzymes play in underpinning genome duplication, aiding replication fork movement in the face of the many replisome barriers that challenge genome stability. These links have many conserved features across all domains of life, reflecting the conserved nature of the substrate for these reactions, DNA.

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Mms1 is an assistant for regulating G-quadruplex DNA structures

Schwindt

Paeschke

2017

Curr Genet

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The preservation of genome stability is fundamental for every cell. Genomic integrity is constantly challenged. Among those challenges are also non-canonical nucleic acid structures. In recent years, scientists became aware of the impact of G-quadruplex (G4) structures on genome stability. It has been shown that folded G4-DNA structures cause changes in the cell, such as transcriptional up/down-regulation, replication stalling, or enhanced genome instability. Multiple helicases have been identified to regulate G4 structures and by this preserve genome stability. Interestingly, although these helicases are mostly ubiquitous expressed, they show specificity for G4 regulation in certain cellular processes (e.g., DNA replication). To this date, it is not clear how this process and target specificity of helicases are achieved. Recently, Mms1, an ubiquitin ligase complex protein, was identified as a novel G4-DNA-binding protein that supports genome stability by aiding Pif1 helicase binding to these regions. In this perspective review, we discuss the question if G4-DNA interacting proteins are fundamental for helicase function and specificity at G4-DNA structures.

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Mms1 and Mms22 stabilize the replisome during replication stress

Abstract: A mechanism is shown by which Mms1 and Mms22 promote DNA replication in the presence of replication stress: they stabilize the replisome at stalled replication forks.

Cited by 20 publications

References 76 publications

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

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

Recombination and Replication

Mms1 is an assistant for regulating G-quadruplex DNA structures

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