Interaction between human Ctf4 and the Cdc45/Mcm2-7/GINS (CMG) replicative helicase

Kang, Young‐Hoon; Farina, Andrea; Bermudez, Vladimir P.; Tappin, Inger; Du, Fang; Galal, Wiebke Chemnitz; Hurwitz, Jerard

doi:10.1073/pnas.1320202110

Cited by 44 publications

(47 citation statements)

References 30 publications

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“…Yeast Ctf4 forms a functional trimer that acts as a multivalent interface between the MCM2-7 helicase-associated GINS complex and DNA-polα during replication (29). This interaction is mediated through specific recognition of a peptide motif found in DNA-polα and Sld5 with the α-helical fold of Ctf4 (29,34,35). We confirmed an interaction between plant EOL1 and SLD5 (Fig.…”

Section: Discussionsupporting

confidence: 73%

“…Although EOL1 is annotated as an unknown protein in The Arabidopsis Information Resource (TAIR), analysis of the primary sequence by SMART (33) predicts the presence of an amino-terminal WD40 domain and a centrally located domain of unknown function (DUF) 3639. This domain structure is found in yeast Ctf4 and metazoan Actinodin 1 (AND1)/ WD-and-High-mobility-group-domain protein 1 (WDHD1), components of the nuclear DNA replisome (34,35). A recently solved crystal structure of Ctf4 showed that DUF3639 is part of a novel WD40-related domain that forms a β-propeller with six blades (β-6-prop), forming a stable trimer (29).…”

Section: Resultsmentioning

confidence: 99%

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Ctf4-related protein recruits LHP1-PRC2 to maintain H3K27me3 levels in dividing cells in Arabidopsis thaliana

Zhou

Tergemina

Cui

et al. 2017

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

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Polycomb Repressive Complex (PRC) 2 catalyzes the H3K27me3 modification that warrants inheritance of a repressive chromatin structure during cell division, thereby assuring stable target gene repression in differentiated cells. It is still under investigation how H3K27me3 is passed on from maternal to filial strands during DNA replication; however, cell division can reinforce H3K27me3 coverage at target regions. To identify novel factors involved in the Polycomb pathway in plants, we performed a forward genetic screen for enhancers of the like heterochromatin protein 1 (lhp1) mutant, which shows relatively mild phenotypic alterations compared with other plant PRC mutants. We mapped enhancer of lhp1 (eol) 1 to a gene related to yeast Chromosome transmission fidelity 4 (Ctf4) based on phylogenetic analysis, structural similarities, physical interaction with the CMG helicase component SLD5, and an expression pattern confined to actively dividing cells. A combination of eol1 with the curly leaf (clf) allele, carrying a mutation in the catalytic core of PRC2, strongly enhanced the clf phenotype; furthermore, H3K27me3 coverage at target genes was strongly reduced in eol1 clf double mutants compared with clf single mutants. EOL1 physically interacted with CLF, its partially redundant paralog SWINGER (SWN), and LHP1. We propose that EOL1 interacts with LHP1-PRC2 complexes during replication and thereby participates in maintaining the H3K27me3 mark at target genes.Ctf4 | epigenetic inheritance | ENHANCER OF LHP1 1 | Polycomb repressive complex 2 | replication

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Section: Discussionsupporting

confidence: 73%

Section: Resultsmentioning

confidence: 99%

Ctf4-related protein recruits LHP1-PRC2 to maintain H3K27me3 levels in dividing cells in Arabidopsis thaliana

Zhou

Tergemina

Cui

et al. 2017

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

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“…ChIP analysis with antibody against the p125 subunit showed that PDIP46 was present together with two components of the mammalian replisome [56]. These are Mcm2, a component of the CMG (Cdc45-MCM-GINS) helicase [151], and Ctf4, which associates with CMG [152,153]. Thus, the ChIP data supports the idea that PDIP46 is associated with chromatin at or near the replisome.…”

Section: Evidence That Pdip46 Is Associated With Pol δ In Vivosupporting

confidence: 69%

Regulation and Modulation of Human DNA Polymerase δ Activity and Function

Lee

Wang

Zhang

et al. 2017

Preprint

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This review focuses on the regulation and modulation of human DNA polymerase δ (Pol δ). The emphasis is on mechanisms that regulate the activity and properties of Pol δ in DNA repair and replication. The areas covered are the degradation of the p12 subunit of Pol δ, which converts it from a heterotetramer (Pol δ4) to a heterotrimer (Pol δ3), in response to DNA damage and also during the cell cycle. The biochemical mechanisms that lead to degradation of p12 are reviewed, as well as the properties of Pol δ4 and Pol δ3 that provide insights into their functions in DNA replication and repair. The second focus of the review involves the functions of two Pol δ binding proteins, PDIP46 and PDIP38, both of which are multi-functional proteins. PDIP46 is a novel activator of Pol δ4, and the impact of this function is discussed in relation to its potential roles in DNA replication. Several new models for the roles of Pol δ3 and Pol δ4 in leading and lagging strand DNA synthesis that integrate a role for PDIP46 are presented. PDIP38 has multiple cellular localizations including the mitochondria, the splicesosomes and the nucleus. It has been implicated in a number of cellular functions, including the regulation of specialized DNA polymerases, mitosis, the DNA damage response, Mdm2 alternative splicing and the regulation of the Nox4 NADPH oxidase.

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“…Recruitment of DNA polymerase ␣ involves its tethering to replisomes and CMG helicases by Ctf4/And1 (45)(46)(47)(48). Sperm chromatin was incubated with extracts in the presence or absence of F1, F2, or exon 5 peptides, and replisomes were allowed to assemble, followed by the isolation of chromatin and extraction with detergent buffer.…”

Section: Resultsmentioning

confidence: 99%

The N Terminus of the Retinoblastoma Protein Inhibits DNA Replication via a Bipartite Mechanism Disrupted in Partially Penetrant Retinoblastomas

Borysov

Nepon-Sixt

Alexandrow

2016

Molecular and Cellular Biology

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The N-terminal domain of the retinoblastoma (Rb) tumor suppressor protein (RbN) harbors in-frame exon deletions in partially penetrant hereditary retinoblastomas and is known to impair cell growth and tumorigenesis. However, how such RbN deletions contribute to Rb tumor-and growth-suppressive functions is unknown. Here we establish that RbN directly inhibits DNA replication initiation and elongation using a bipartite mechanism involving N-terminal exons lost in cancer. Specifically, Rb exon 7 is necessary and sufficient to target and inhibit the replicative CMG helicase, resulting in the accumulation of inactive CMGs on chromatin. An independent N-terminal loop domain, which forms a projection, specifically blocks DNA polymerase ␣ (Pol-␣) and Ctf4 recruitment without affecting DNA polymerases and ␦ or the CMG helicase. Individual disruption of exon 7 or the projection in RbN or Rb, as occurs in inherited cancers, partially impairs the ability of Rb/RbN to inhibit DNA replication and block G 1 -to-S cell cycle transit. However, their combined loss abolishes these functions of Rb. Thus, Rb growth-suppressive functions include its ability to block replicative complexes via bipartite, independent, and additive N-terminal domains. The partial loss of replication, CMG, or Pol-␣ control provides a potential molecular explanation for how N-terminal Rb loss-offunction deletions contribute to the etiology of partially penetrant retinoblastomas. Mutational inactivation or deletion of the retinoblastoma (Rb) tumor suppressor gene occurs in multiple cancer types, including retinoblastoma, osteosarcoma, and breast and small cell lung cancers, and deregulation or inactivation of regulatory components of the Rb pathway is a hallmark of human cancers (1). The Rb protein functions to harness a variety of cellular processes important in tumorigenesis, including regulation of the cell cycle, apoptosis, differentiation, stress responses, and DNA replication. The role of Rb in these processes derives to a large extent from interactions of proteins with the C terminus of Rb that contains a large pocket domain (1-5), and most Rb loss-of-function mutations compromise pocket structure and/or function and are highly penetrant alleles of inherited cancer in humans and mice (6).Multiple observations indicate that the N-terminal domain of Rb (RbN) (residues 1 to 400) also plays an important role in growth suppression and tumorigenesis. Indeed, nearly 20% of cancer-associated in-frame mutations in Rb are located in the Nterminal region (6). These lesions leave an intact C-terminal pocket and generate stable forms of Rb that bind E2F transcription factors and localize to the nucleus in a fashion similar to that of wild-type Rb (wt-Rb) (6-10). Several in-frame RbN exon deletions in familial retinoblastomas have been reported, including individual losses of exon 4 (Ex4), Ex5, Ex7,. Inframe deletions and mutations have also been found in Rb exons 6 and 8 in prostate cancers and astrocytomas, respectively (15, 16). Furthermore, in contrast to pock...

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Interaction between human Ctf4 and the Cdc45/Mcm2-7/GINS (CMG) replicative helicase

Cited by 44 publications

References 30 publications

Ctf4-related protein recruits LHP1-PRC2 to maintain H3K27me3 levels in dividing cells in Arabidopsis thaliana

Ctf4-related protein recruits LHP1-PRC2 to maintain H3K27me3 levels in dividing cells in Arabidopsis thaliana

Regulation and Modulation of Human DNA Polymerase δ Activity and Function

The N Terminus of the Retinoblastoma Protein Inhibits DNA Replication via a Bipartite Mechanism Disrupted in Partially Penetrant Retinoblastomas

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Interaction between human Ctf4 and the Cdc45/Mcm2-7/GINS (CMG) replicative helicase

Cited by 44 publications

References 30 publications

Ctf4-related protein recruits LHP1-PRC2 to maintain H3K27me3 levels in dividing cells in Arabidopsis thaliana

Ctf4-related protein recruits LHP1-PRC2 to maintain H3K27me3 levels in dividing cells in Arabidopsis thaliana

Regulation and Modulation of Human DNA Polymerase &delta; Activity and Function

The N Terminus of the Retinoblastoma Protein Inhibits DNA Replication via a Bipartite Mechanism Disrupted in Partially Penetrant Retinoblastomas

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Regulation and Modulation of Human DNA Polymerase δ Activity and Function