Proliferating cell nuclear antigen (PCNA), or cyclin, is a non-histone acidic nuclear protein []that plays a key role in the control of eukaryotic DNA replication []. It acts as a co-factor for DNA polymerase delta, which is responsible for leading strand DNAreplication []. The sequence of PCNA is well conserved between plants and animals, indicating a strong selective pressure for structure conservation, and suggesting that this type of DNA replication mechanism is conserved throughout eukaryotes []. In Saccharomyces cerevisiae (Baker's yeast), POL30, is associated with polymerase III, the yeast analog of polymerase delta.Homologues of PCNA have also been identified in the archaea (known as DNA polymerase sliding clamp) [, ]and in Paramecium bursaria Chlorella virus 1 (PBCV-1) and in nuclear polyhedrosis viruses.
This entry includes Rad18 from eukaryotes. Rad18 is a E3 ubiquitin ligase required for postreplication repair []. In budding yeast, Rad18 forms a heterodimer with Rad6 to monoubiquitinate PCNA at a highly conserved lysine, 'Lys-164' []. In humans, Rad18 associates to the E2 ubiquitin conjugating enzyme UBE2B to form the UBE2B-RAD18 ubiquitin ligase complex involved in mono-ubiquitination of DNA-associated PCNA on 'Lys-164' [].
PCNA-interacting partner (also known as PARI) is an antirecombinase. It interacts with PCNA and inhibits homologous recombination []. It also modulates stalled fork processing, which is required for stable genome inheritance under both endogenous and exogenous replication stress [].
Proliferating cell nuclear antigen (PCNA), or cyclin, is a non-histone acidic nuclear protein []that plays a key role in the control of eukaryotic DNA replication []. It acts as a co-factor for DNA polymerase delta, which is responsible for leading strand DNAreplication []. The sequence of PCNA is well conserved between plants and animals, indicating a strong selective pressure for structure conservation, and suggesting that this type of DNA replication mechanism is conserved throughout eukaryotes []. In Saccharomyces cerevisiae (Baker's yeast), POL30, is associated with polymerase III, the yeast analog of polymerase delta.Homologues of PCNA have also been identified in the archaea (known as DNA polymerase sliding clamp) [, ]and in Paramecium bursaria Chlorella virus 1 (PBCV-1) and in nuclear polyhedrosis viruses. The N-terminal and C-terminal domains of PCNA are topologically identical. Three PCNA molecules are tightly associated to form a closed ring encircling duplex DNA [].
Proliferating cell nuclear antigen (PCNA), or cyclin, is a non-histone acidic nuclear protein []that plays a key role in the control of eukaryotic DNA replication []. It acts as a co-factor for DNA polymerase delta, which is responsible for leading strand DNAreplication []. The sequence of PCNA is well conserved between plants and animals, indicating a strong selective pressure for structure conservation, and suggesting that this type of DNA replication mechanism is conserved throughout eukaryotes []. In Saccharomyces cerevisiae (Baker's yeast), POL30, is associated with polymerase III, the yeast analog of polymerase delta.Homologues of PCNA have also been identified in the archaea (known as DNA polymerase sliding clamp) [, ]and in Paramecium bursaria Chlorella virus 1 (PBCV-1) and in nuclear polyhedrosis viruses. The N-terminal and C-terminal domains of PCNA are topologically identical. Three PCNA molecules are tightly associated to form a closed ring encircling duplex DNA [].
This is the C-terminal domain of replication factor C, RFC1. RFC complexes hydrolyse ATP and load sliding clamps such as PCNA (proliferating cell nuclear antigen) onto double-stranded DNA. RFC1 is essential for RFC function in vivo [, ].
Replication factor C (RFC) is a multimeric AAA+ protein complex that loads the DNA polymerase processivity clamp PCNA (Proliferating Cell Nuclear Antigen) onto DNA using ATP to drive the reaction []. PCNA functions at multiple levels in directing DNA metabolic pathways []. When bound to DNA, PCNA organises various proteins involved in DNA replication, DNA repair, DNA modification, and chromatin modelling.In contrast to eukaryotic RFC, which has been shown to contain five distinct polypeptides, archaeal RFC contains only two types of subunit - large and small. The exact subunit stoichiometry in archaea is unclear. In Methanobacterium thermoautotrophicum, RFC is reported to be a heterohexamer, composed of four small and two large subunits []. In Sulfolobus solfataricus, meanwhile, it is reported to be a heteropentamer of four small subunits and one large [].This entry represents the archaeal RFC small subunit.
This family consists of several baculovirus occlusion-derived virus envelope proteins (EC27 orE27) which appear to act as a multifuntional cyclins during the host cell cycle. The ODV-E27 protein has distinct functional characteristics compared to cellular and viralcyclins. When associated with cdc2, itexhibits cyclin B-like activity; when associated with cdk6, the complex possesses cyclin D-like activity and binds PCNA (proliferating cell nuclear antigen) [].
This entry represents archaeal Nre proteins. While most archaeal organisms encode only a single Nre protein, some encode two, NreA and NreB.NreA is an archaeal PCNA interacting protein that works together with the UvrABC proteins in repairing DNA damage resulting from exposure to DNA damaging agent MMC. NreA contains a putative PIP motif at its C terminus that is important for its function [].
These proteins are part of the RFC clamp loader complex, which loads the PCNA sliding clamp onto DNA. The large subunits (RfcL) form a heteromultimer with small subunits (RfcS). Proteins in this entry belong to the activator 1 small subunit family RfcL subfamily.
This family of proteins represents the catalytic subunit, Pol, of the Herpes simplex virus DNA polymerase. Pol binds UL42, making up the DNA polymerase. UL42 is a processivity subunit which binds to the C-terminal of Pol in a similar way that the cell cycle regulator p21 binds to PCNA [].
Proliferating cell nuclear antigen (PCNA), or cyclin, is a non-histone acidic nuclear protein []that plays a key role in the control of eukaryotic DNA replication []. It acts as a co-factor for DNA polymerase delta, which is responsible for leading strand DNAreplication []. The sequence of PCNA is well conserved between plants and animals, indicating a strong selective pressure for structure conservation, and suggesting that this type of DNA replication mechanism is conserved throughout eukaryotes []. In Saccharomyces cerevisiae (Baker's yeast), POL30, is associated with polymerase III, the yeast analog of polymerase delta.Homologues of PCNA have also been identified in the archaea (known as DNA polymerase sliding clamp) [, ]and in Paramecium bursaria Chlorella virus 1 (PBCV-1) and in nuclear polyhedrosis viruses. This entry represents two conserved regions located in the N-terminal section. The second one has been proposed to bind DNA.
This conserved region is found in the N-terminal region of archaeal Nre proteins. While most archaeal organisms encode only a single Nre protein, some encode two, NreA and NreB. NreA is an archaeal PCNA interacting protein that works together with the UvrABC proteins in repairing DNA damage resulting from exposure to DNA damaging agent MMC. NreA contains a putative PIP motif at its C terminus that is important for its function [].
This conserved region is found in the C-terminal region of archaeal Nre proteins. While most archaeal organisms encode only a single Nre protein, some encode two, NreA and NreB. NreA is an archaeal PCNA interacting protein that works together with the UvrABC proteins in repairing DNA damage resulting from exposure to DNA damaging agent MMC. NreA contains a putative PIP motif atits C terminus that is important for its function [].
This is the C-terminal domain of RFC (replication factor-C) protein of the clamp loader complex which binds to the DNA sliding clamp (proliferating cell nuclear antigen, PCNA). The five modules of RFC assemble into a right-handed spiral, which results in only three of the five RFC subunits (RFC-A, RFC-B and RFC-C) making contact with PCNA, leaving a wedge-shaped gap between RFC-E and the PCNA clamp-loader complex. The C-terminal is vital for the correct orientation of RFC-E with respect to RFC-A [].
This entry consists of the human Hus1 protein and budding yeast Mec3. They are components of the checkpoint clamp complex involved in the surveillance mechanism that allows the DNA repair pathways to act to restore the integrity of the DNA prior to DNA synthesis or separation of the replicated chromosomes [, ]. Hus1, Rad1, and Rad9 (which share homology with Mec1, Rad17, Ddc1 in budding yeast) are three evolutionarily conserved proteins required for checkpoint control. These proteins are known to form a stable complex. Structurally, the Ddc1-Mec3-Rad17 complex is similar to the PCNA complex, which forms trimeric ring-shaped clamps. Ddc1-Mec3-Rad17 plays a role in checkpoint activation that permits DNA-repair pathways to prevent cell cycle progression in response to DNA damage and replication stress [, ].
Peptidase C19 contains ubiquitin hydrolases. They are intracellular peptidases that remove ubiquitin molecules from polyubiquitinated peptides by cleavage of isopeptide bonds. They hydrolyze bonds involving the carboxyl group of the C-terminal Gly residue of ubiquitin. The purpose of the de-ubiquitination is thought to be editing of the ubiquitin conjugates, which could rescue them from degradation, as well as recycling of the ubiquitin. The ubiquitin/proteasome system is responsible for most protein turnover in the mammalian cell, and with over 50 members, family C19 is one of the largest families of peptidases in the human genome [, ].This entry encompasses ubiquitin-specific hydrolase 1 (MEROPS identifier C19.019). It is required for deubiquitination of monoubiquitinated proteins involved in various DNA repair pathways and is a key regulator of DNA repair mechanisms []. Substrates include monoubiquitinated PCNA [], and components FANCD2 []and FANCI []of the Fanconi anemia pathway, a genetic disorder that resultsin the inability to monoubiquitinate these components [].
This entry includes PAX-interacting protein 1 (PTIP or Swift) and chromatin modification-related protein eaf1 (from Aspergillus fumigatus). PTIP is involved in the DNA damage response and is an adaptor protein for the ATM/ATR kinases. PTIP contains five BRCT domains with which it interacts with the activation domain of the transcription factor Pax2 []. Knockout of PTIP prevent ubiquitination of proliferating cell nuclear antigen (PCNA), and monoubiquitination of PCNA enables translesion synthesis by specialized DNA polymerases to replicate damaged DNA []. Cells without PTIP are unable to progress through mitosis []. PTIP is a component of the MLL2/MLL3 complex [], but a PTIP-PA1 subcomplex functions independently of the MLL3/MLL4 complex to mediate transcription during class switch recombination, important for generating antibody diversity []. In Saccharomyces cerevisiae, EAF1 is a component of the NuA4 histone acetyltransferase complex involved in acetylation of nucleosomal histone H4 and H2A [].
This entry represents the DNA damage checkpoint protein Rad9 and its homologue in budding yeast, Ddc1. Rad9 forms a complex with Hus1 and Rad1 (called 9-1-1 complex). Ddc1 forms a similar complex with Mec1 and Rad17. Structurally, the 9-1-1 / Ddc1-Mec3-Rad17 complex is similar to the PCNA complex, which forms trimeric ring-shaped clamps. The 9-1-1 / Ddc1-Mec3-Rad17 complex plays a role in checkpoint activation that permits DNA-repair pathways to prevent cell cycle progression in response to DNA damage and replication stress [, ].In humans, 9-1-1 binds to TopBP1 and activates the ATR-Chk1 checkpoint pathway []. Besides its function in the 9-1-1 complex, Rad9 can also act as a transcriptional factor and participate in immunoglobulin class switch recombination []. It also shows 3'-5' exonuclease activity []. Aberrant Rad9 expression has been associated with prostate, breast, lung, skin, thyroid, and gastric cancers [].In budding yeast, Ddc1 can activate Mec1 (the principal checkpoint protein kinase, human ATR homologue) in G1 phase. In G2 phase, Ddc1 can either activate Mec1 directly or recruit Dpb11 (the orthologue of human TopBP1) and subsequently activate Mec1 []. Ddc1 does not have DNA exonuclease function [].It is worth noting that the Rad9 proteins referred to in this entry are the mammalian and fission yeast homologues of budding yeast Ddc1. Members of this family do not share the sequence homology another DNA damage-dependent checkpoint protein from budding yeast, confusingly also called Rad9.
DNA replication in eukaryotes results from a highly coordinated interaction between proteins, often as part of protein complexes, and the DNA template. One of the key early steps leading to DNA replication is formation of the pre-replication complex, or pre-RC. The pre-RC is formed by the sequential binding of the origin recognition complex (ORC), Cdc6 and Cdt1 proteins, and the MCM complex. Activation of the pre-RC into the initiation complex (IC) is achieved via the action of S-phase kinases, eventually leading to the loading of the replication machinery.Recently, a novel replication complex, GINS (for Go, Ichi, Nii, and San; five, one, two, and three in Japanese), has been identified [, ]. The precise function of GINS is not known. However, genetic and two-hybrid interactions indicate that it mediates the loading of the enzymatic replication machinery at a step after the action of the S-phase kinases []. Furthermore, GINS may be a part of the replication machinery itself, since it is found associated with replicating DNA [, ]. Electron microscopy of GINS shows that it forms a ring-like structure [], reminiscent of the structure of PCNA [], the DNA polymerase delta replication clamp. This observation, coupled with the observed interactions for GINS, indicates that the complex may represent the replication clamp for DNA polymerase epsilon [].The GINS complex is essential for initiation of DNA replication in Xenopus egg extracts []. This 100kDa stable complex includes Sld5, Psf1, Psf2, and Psf3. Homologues of these components are found also in other eukaryotes. This superfamily represents the Psf3 component.
DNA replication in eukaryotes results from a highly coordinated interaction between proteins, often as part of protein complexes, and the DNA template. One of the key early steps leading to DNA replication is formation of the pre-replication complex, or pre-RC. The pre-RC is formed by the sequential binding of the origin recognition complex (ORC), Cdc6 and Cdt1 proteins, and the MCM complex. Activation of the pre-RC into the initiation complex (IC) is achieved via the action of S-phase kinases, eventually leading to the loading of the replication machinery.Recently, a novel replication complex, GINS (for Go, Ichi, Nii, and San; five, one, two, and three in Japanese), has been identified [, ]. The precise function of GINS is not known. However, genetic and two-hybrid interactions indicate that it mediates the loading of the enzymatic replication machinery at a step after the action of the S-phase kinases []. Furthermore, GINS may be a part of the replication machinery itself, since it is found associated with replicating DNA [, ]. Electron microscopy of GINS shows that it forms a ring-like structure [], reminiscent of the structure of PCNA [], the DNA polymerase delta replication clamp. This observation, coupled with the observed interactions for GINS, indicates that the complex may represent the replication clamp for DNA polymerase epsilon [].The GINS complex is essential for initiation of DNA replication in Xenopusegg extracts []. This 100kDa stable complex includes Sld5, Psf1, Psf2, and Psf3. Homologues of these components are found also in other eukaryotes. This family of proteins represents the Psf3 component.
DNA replication in eukaryotes results from a highly coordinated interaction between proteins, often as part of protein complexes, and the DNA template. One of the key early steps leading to DNA replication is formation of the prereplication complex, or pre-RC. The pre-RC is formed by the sequential binding of the origin recognition complex (ORC), Cdc6 and Cdt1 proteins, and the MCM complex. Activation of the pre-RC into the initiation complex (IC) is achieved via the action of S-phase kinases, eventually leading to the loading of the replication machinery.Recently, a novel replication complex, GINS (for Go, Ichi, Nii, and San; five, one, two, and three in Japanese), has been identified [, ]. The precise function of GINS is not known. However, genetic and two-hybrid interactions indicate that it mediates the loading of the enzymatic replication machinery at a step after the action of the S-phase kinases []. Furthermore, GINS may be a part of the replication machinery itself, since it is found associated with replicating DNA [, ]. Electron microscopy of GINS shows that it forms a ring-like structure [], reminiscent of the structure of PCNA [], the DNA polymerase delta replication clamp.This observation, coupled with the observed interactions for GINS, indicates that the complex may represent the replication clamp for DNA polymerase epsilon [].The GINS complex is essential for initiation of DNA replication in Xenopus egg extracts []. This 100kDa stable complex includes Sld5, Psf1, Psf2, and Psf3. Homologues of these components are found also in other eukaryotes. This family of proteins represents the Psf2 component.
Chromatin assembly factor 1 (CAF-1) consists of three evolutionary conserved subunits, p150, p60, and p48 (yeast homologues Cac1, cac2 and cac3 respectively), and mediates the assembly of nucleosomes onto newly replicated DNA. The p150 subunit (CAF-1_p150, also known as subunit A) is the core component of the CAF-1 histone chaperone complex, which functions in depositing newly synthesised and acetylated histones H3/H4 into chromatin during DNA replication and repair [, ], being essential for cell viability and efficient DNA replication. The p150 subunit contains the interaction regions with proliferating cell nuclear antigen (PCNA), heterochromatin protein 1 (HP1), the CAF-1 p60 subunit among others proteins []. It is thought that the DNA association with two histone-bound CAF-1 complexes may promote the formation of the (H3-H4)2 tetramer on DNA [].This entry represents the N-terminal region of the CAF-1 subunit p150 that contains one of the PCNA (proliferating cell nuclear antigen) binding sites, designated PIP1 and the heterochromatin protein 1 (HP1) interacting domain MIR []. These domains are dispensable for p150 role in nucleosome assembly and it is thought that this N-terminal region of CAF-1 might act as a regulatory domain contributing to CAF-1-PCNA interaction stability or mediate other functions during DNA repair or heterochromatin maintenance [].
DNA replication in eukaryotes results from a highly coordinated interaction between proteins, often as part of protein complexes, and the DNA template. One of the key early steps leading to DNA replication is formation of the prereplication complex, or pre-RC. The pre-RC is formed by the sequential binding of the origin recognition complex (ORC), Cdc6 and Cdt1 proteins, and the MCM complex. Activation of the pre-RC into the initiation complex (IC) is achieved via the action of S-phase kinases, eventually leading to the loading of the replication machinery.Recently, a novel replication complex, GINS (for Go, Ichi, Nii, and San; five, one, two, and three in Japanese), has been identified [, ]. The precise function of GINS is not known. However, genetic and two-hybrid interactions indicate that it mediates the loading of the enzymatic replication machinery at a step after the action of the S-phase kinases []. Furthermore, GINS may be a part of the replication machinery itself, since it is found associated with replicating DNA [, ]. Electron microscopy of GINS shows that it forms a ring-like structure [], reminiscent of the structure of PCNA [], the DNA polymerase delta replication clamp.This observation, coupled with the observed interactions for GINS, indicates that the complex may represent the replication clamp for DNA polymerase epsilon [].This family of proteins represents the PSF1 component (for partner of SLD five) of the GINS complex.
DNA replication in eukaryotes results from a highly coordinated interaction between proteins, often as part of protein complexes, and the DNA template. One of the key early steps leading to DNA replication is formation of the pre-replication complex, or pre-RC. The pre-RC is formed by the sequential binding of the origin recognition complex (ORC), Cdc6 and Cdt1 proteins, and the MCM complex. Activation of the pre-RC into the initiation complex (IC) is achieved via the action of S-phase kinases, eventually leading to the loading of the replication machinery.Recently, a novel replication complex, GINS (for Go, Ichi, Nii, and San; five, one, two, and three in Japanese), has been identified [, ]. The precise function of GINS is not known. However, genetic and two-hybrid interactions indicate that it mediates the loading of the enzymatic replication machinery at a step after the action of the S-phase kinases []. Furthermore, GINS may be a part of the replication machinery itself, since it is found associated with replicating DNA [, ]. Electron microscopy of GINS shows that it forms a ring-like structure [], reminiscent of the structure of PCNA [], the DNA polymerase delta replication clamp. This observation, coupled with the observed interactions for GINS, indicates that the complex may represent the replication clamp for DNA polymerase epsilon [].The GINS complex is essential for initiation of DNA replication in Xenopus egg extracts []. This 100kDa stable complex includes Sld5, Psf1, Psf2, and Psf3. Homologues of these components are found also in other eukaryotes []. The archaeal GINS complex contains two subunits (SSO0772/gins23 and SO1049/gins15 in Sulfolobus) that are poorly conserved homologues of the eukaryotic GINS subunits []. Only Gins23 is included in this entry.The eukaryotic GINS subunits are homologous. The four subunits of the complex consist of two domains each, termed the α-helical (A) and β-strand (B) domains. The A and B domains of Sld5/Psf1 are permuted with respect to Psf1/Psf3 [].
DNA replication in eukaryotes results from a highly coordinated interaction between proteins, often as part of protein complexes, and the DNA template. One of the key early steps leading to DNA replication is formation of the pre-replication complex, or pre-RC. The pre-RC is formed by the sequential binding of the origin recognition complex (ORC), Cdc6 and Cdt1 proteins, and the MCM complex. Activation of the pre-RC into the initiation complex (IC) is achieved via the action of S-phase kinases, eventually leading to the loading of the replication machinery.Recently, a novel replication complex, GINS (for Go, Ichi, Nii, and San; five, one, two, and three in Japanese), has been identified [, ]. The precise function of GINS is not known. However, genetic and two-hybrid interactions indicate that it mediates the loading of the enzymatic replication machinery at a step after the action of the S-phase kinases []. Furthermore, GINS may be a part of the replication machinery itself, since it is found associated with replicating DNA [, ]. Electron microscopy of GINS shows that it forms a ring-like structure [], reminiscent of the structure of PCNA [], the DNA polymerase delta replication clamp. This observation, coupled with the observed interactions for GINS, indicates that the complex may represent the replication clamp for DNA polymerase epsilon [].The GINS complex is essential for initiation of DNA replication in Xenopus egg extracts []. This 100kDa stable complex includes Sld5, Psf1, Psf2, and Psf3. Homologues of these components are found also in other eukaryotes []. The archaeal GINS complex contains two subunits (SSO0772/gins23 and SO1049/gins15 in Sulfolobus) that are poorly conserved homologues of the eukaryotic GINS subunits []. Only Gins23 is included in this entry.The eukaryotic GINS subunits are homologous. The four subunits of the complex consist of two domains each, termed the α-helical (A) and β-strand (B) domains. The A and B domains of Sld5/Psf1 are permuted with respect to Psf1/Psf3 [].
