Elg1 Forms an Alternative PCNA-Interacting RFC Complex Required to Maintain Genome Stability

Kanellis, Pamela; Agyei, Roger; Durocher, Daniel

doi:10.1016/s0960-9822(03)00578-5

Cited by 152 publications

(218 citation statements)

References 49 publications

(6 reference statements)

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“…However, this simple argument ignores the complexity of interactions of the Rfc2-5 core, which can function in at least four distinct clamp loaders typified by RFC1, RAD24, CTF18, and ELG1 (23)(24)(25)(26)(27). Mutations in the latter two genes directly or indirectly affect DNA damage response and checkpoint function, and it is possible that the observed phenotypic defects of the RFC4 mutations carry additional contributions from possible defects in the function of the CTF18 and ELG1 clamp loaders (26 -28).…”

Section: Discussionmentioning

confidence: 99%

Requirement for ATP by the DNA Damage Checkpoint Clamp Loader

Majka

Chung

Burgers

2004

Journal of Biological Chemistry

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The DNA damage clamp loader replication factor C (RFC-Rad24) consists of the Rad24 protein and the four small Rfc2-5 subunits of RFC. This complex loads the heterotrimeric DNA damage clamp consisting of Rad17, Mec3, and Ddc1 (Rad17/3/1) onto partial duplex DNA in an ATP-dependent manner. Interactions between the clamp loader and the clamp have been proposed to mirror those of the replication clamp loader RFC and the sliding clamp proliferating cell nuclear antigen (PCNA). In that system, three ATP molecules bound to the Rfc2, Rfc3, and Rfc4 subunits are necessary and sufficient for efficient loading of PCNA, whereas ATP binding to Rfc1 is not required. In contrast, in this study, we show that mutant RFC-Rad24 with a rad24-K115E mutation in the ATP-binding domain of Rad24 shows defects in the ATPase of the complex and is defective for interaction with Rad17/3/1 and for loading of the checkpoint clamp. A similar defect was measured with a mutant RFCRad24 clamp loader carrying a rfc4K55R ATP-binding mutation, whereas the rfc4K55E clamp loader showed partial loading activity, in agreement with genetic studies of these mutants. These studies show that ATP utilization by the checkpoint clamp/clamp loader system is effectively different from that by the structurally analogous replication system.

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Section: Discussionmentioning

confidence: 99%

Requirement for ATP by the DNA Damage Checkpoint Clamp Loader

Majka

Chung

Burgers

2004

Journal of Biological Chemistry

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“…Thus, Elg1p-Rfc2-5p functions to maintain genome stability during normal cell growth. The synthetic growth defect of the elg1 strain by the mutation of homologous recombination (HR) repair genes (rad51, rad52, rad54, rad55, rad57, and mre11) suggests that the lack of Elg1p-Rfc2-5p would create DSBs that HR proteins need to repair [12]. Although Elg1p's function is not essential for viability in yeast, the replication .…”

Section: Elg1 Functions In Dna Replication To Suppress Gcrmentioning

confidence: 99%

“…Possible molecular functions of Elg1p-Rfc2-5p for maintaining genome stability Elg1p interacts with PCNA and Rad27p (yeast homolog of human FEN1, FLAP endonuclease) that removes the flap structure at the lagging strand during DNA replication [12]. Therefore, Elg1p-Rfc2-5p may play an important role during DNA replication to protect the genome by loading or unloading a clamp similar to other RFCs' roles.…”

Section: Elg1 Functions In Dna Replication To Suppress Gcrmentioning

confidence: 99%

“…Therefore, Elg1p-Rfc2-5p may play an important role during DNA replication to protect the genome by loading or unloading a clamp similar to other RFCs' roles. Despite negative in vitro PCNA loading or unloading PCNA by Elg1p-Rfc2-5p [9], the physical interaction of Elg1p with PCNA [12] strongly suggests Elg1p-Rfc2-5p as a PCNA loader or unloader. The PCNA loading/unloading activity of Elg1p-Rfc2-5p seems to overlap with other RFCs because synergistic sensitivities to DNA damaging agents were observed by inactivation of other RFCs with Elg1p-Rfc2-5p [11;12].…”

Section: Elg1 Functions In Dna Replication To Suppress Gcrmentioning

confidence: 99%

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Suppression of gross chromosomal rearrangements by a new alternative replication factor C complex

Banerjee

Sikdar

Myung

2007

Biochemical and Biophysical Research Communications

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Defects in DNA replication fidelity lead to genomic instability. Gross chromosomal rearrangement (GCR), a type of genomic instability, is highly enhanced by various initial mutations affecting DNA replication. Frequent observations of GCRs in many cancers strongly argue the importance to maintain high fidelity of DNA replication to suppress carcinogenesis. Recent genome wide screens in Saccharomyces cerevisiae identified a new GCR suppressor gene, ELG1, enhanced level of genome instability gene 1. Its physical interaction with proliferating cell nuclear antigen (PCNA) and complex formation with Rfc2-5p proteins suggest that Elg1 functions to load/unload PCNA onto DNA during a certain DNA metabolism. High level of DNA damage accumulation and enhanced phenotypes with mutations in genes involved in cell cycle checkpoints, homologous recombination (HR), or chromatin assembly in the elg1 strain suggest that Elg1p-Rfc2-5p functions in a fundamental DNA metabolism to suppress genomic instability. KeywordsGenomic instability; DNA replication; ELG1; RFC; PCNA DNA is constantly challenged by intracellular as well as environmental stress. Inaccurate repair of DNA damage by such stress can result in genomic instability that can manifest as gross chromosomal rearrangements (GCRs). GCRs include translocations, deletions, inversions, amplifications, chromosome end-to-end fusions, and aneuploidy [1]. These genetic malformations often lead to cell death or carcinogenesis. Frequent observations of genomic instability in tumor cells support the argument for the importance of proper DNA repair to suppress carcinogenesis.Multiple mutations in cancer normally exceed the expected number of mutations that cells are able to obtain with normal mutation rates. In order to generate multiple mutations, cells must develop specific initial mutations that can facilitate further mutagenesis [2]. These initial mutations, known as mutator mutations, have been suggested to facilitate multiple mutations in many oncogenes and tumor suppressor genes during carcinogenesis. Mutator mutations were first proposed from cases of the hereditary nonpolyposis colorectal cancer Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access A new member of RFC family (ELG1-RFC)Processing of stalled replication forks are usually modulated by a homo-trimeric DNA sliding clamp called PCNA in eukaryotes. Differential post-translational modifications in PCNA have been documented as a regulatory mechanism for many different DNA metabolisms including GCR [5]. Replication factor C (RFC) complex is a heteropentameric ...

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“…Consistent with our hypothesis, the GCR rate of rad5 smc6-9 was comparable to strains having each mutation (Table 5). Lastly, an additional mutation of elg1, which activates DNA damage checkpoint and enhances GCR [7,48], in the smc6-9 strain, synergistically increased the GCR rate (Table 5).…”

Section: Inactivation Of Dna Damage Checkpoints In the Smc6-9 Strain mentioning

confidence: 99%

Smc5–Smc6 complex suppresses gross chromosomal rearrangements mediated by break-induced replications

et al. 2008

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Translocations in chromosomes alter genetic information. Although the frequent translocations observed in many tumors suggest the altered genetic information by translocation could promote tumorigenesis, the mechanisms for how translocations are suppressed and produced are poorly understood. The smc6-9 mutation increased the translocation class gross chromosomal rearrangement (GCR). Translocations produced in the smc6-9 strain are unique because they are nonreciprocal and dependent on break-induced replication (BIR) and independent of non-homologous end joining. The high incidence of translocations near repetitive sequences such as δ sequences, ARS, tRNA genes, and telomeres in the smc6-9 strain indicates that Smc5-Smc6 suppresses translocations by reducing DNA damage at repetitive sequences. Synergistic enhancements of translocations in strains defective in DNA damage checkpoints by the smc6-9 mutation without affecting de novo telomere addition class GCR suggest that Smc5-Smc6 defines a new pathway to suppress GCR formation.

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Elg1 Forms an Alternative PCNA-Interacting RFC Complex Required to Maintain Genome Stability

Abstract: Collectively, these results reveal that Elg1 forms a novel and conserved alternative RFC complex. Furthermore, we propose that genome instability arises at high frequency in elg1 mutants due to a defect in Okazaki fragment maturation.

Cited by 152 publications

References 49 publications

Requirement for ATP by the DNA Damage Checkpoint Clamp Loader

Requirement for ATP by the DNA Damage Checkpoint Clamp Loader

Suppression of gross chromosomal rearrangements by a new alternative replication factor C complex

Smc5–Smc6 complex suppresses gross chromosomal rearrangements mediated by break-induced replications

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