Search results for DDB1

Showing 26 results out of 60

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Protein (6 results from a total of 13)

Identifier: R-HSA-53489
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: DDB1: Q16531
Identifier: R-HSA-8863297
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: DDA1: Q9BW61
Identifier: R-HSA-8955192
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: DCAF8: Q5TAQ9
Identifier: R-HSA-8863252
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: DCAF6: Q58WW2
Identifier: R-HSA-8863312
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: DCAF7: P61962
Identifier: R-HSA-8955189
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: DCAF5: Q96JK2

Complex (6 results from a total of 29)

Identifier: R-HSA-5688955
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-5696680
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-5655461
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-976149
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-6781841
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-6781842
Species: Homo sapiens
Compartment: nucleoplasm

Set (2 results from a total of 2)

Identifier: R-HSA-5655459
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-976118
Species: Homo sapiens
Compartment: nucleoplasm

Reaction (6 results from a total of 9)

Identifier: R-HSA-6781867
Species: Homo sapiens
Compartment: nucleoplasm
The ubiquitin ligase complex ERCC8:DDB1:CUL4:RBX1 may ubiquitinate ERCC6 (CSB) (Groisman et al. 2006) at the later steps of TC-NER and may also be required in the ubiquitination of the RNA Pol II subunit POLR2A in response to damage (Bregman et al. 1996, Lee et al. 2002). Ubiquitination mediated by ERCC8 (CSA) containing ubiquitin ligase complex plays an important role in progression and termination of transcription-coupled nucleotide excision repair (TC-NER), although the mechanistic details are largely unknown.
Identifier: R-HSA-5652009
Species: Homo sapiens
Compartment: nucleoplasm
The complex of RAD18, an E3 ubiquitin ligase, and UBE2B (RAD6), an E2 ubiquitin conjugating enzyme, monoubiquitinates PCNA associated with damaged DNA on lysine residue K164, using the ubiquitin residue K63 to create the covalent bond (Hoege et al. 2002). The catalytic subunit of DNA polymerase delta (POLD), POLD1, does not bind monoubiquitinated PCNA (Park et al. 2014), implying that replicative polymerases POLD and POLE (DNA polymerase epsilon complex) dissociate from PCNA monubiquitinated at K164. This is in accordance with the proposed DNA polymerase switch during translesion DNA synthesis (TLS) (Friedberg et al. 2005). DNA damage induced removal of PCNA-associated protein KIAA0101 (PAF15) through proteasome-mediated degradation facilitates switching from replicative DNA polymerases POLD and POLE to TLS polymerases (Povlsen et al. 2012).

The ubiquitin ligase complex RBX1:CUL4:DDB1:DTL can also monoubiquitinate PCNA. RBX1:CUL4:DDB1:DTL is probably responsible for the basal monoubiquitination of PCNA and may contribute to the kinetics of DNA-damage induced PCNA monoubiquitination (Terai et al. 2010).

Identifier: R-HSA-5652005
Species: Homo sapiens
Compartment: nucleoplasm
The complex of RAD18, an E3 ubiquitin ligase, and UBE2B (RAD6), an E2 ubiquitin-conjugating enzyme, binds the replication complex consisting of PCNA, DNA polymerase complex delta (POLD) or DNA polymerase complex epsilon (POLE), RPA and RFC on damaged dsDNA. RAD18 simultaneously interacts with PCNA, RPA and DNA (Hoege et al. 2002, Notenboom et al. 2007, Davies et al. 2008). The ubiquitin ligase complex RBX1:CUL4:DDB1:DTL can also bind PCNA (Terai et al. 2010).
Identifier: R-HSA-6782943
Species: Homo sapiens
Compartment: nucleoplasm
The role of UV-DDB-mediated ubiquitination in global genome nucleotide excision repair (GG-NER) has not been fully elucidated.

In the absence of DNA damage, the ubiquitin ligase activity of UV-DDB complex is inhibited by association with the COP9 signalosome (CSN complex), which dissociates from the UV-DDB complex upon binding to damaged DNA (Groisman et al. 2003, Fischer et al. 2011). Ubiquitination of XPC by UV-DDB promotes XPC retention at GG-NER sites, while progressive autoubiquitination of UV-DDB promotes the dissociation of UV-DDB from the DNA and may act as an intracellular signal (Sugasawa et al. 2005). The UV-DDB complex also ubiquitinates histones H2A, H3 and H4, which may trigger chromatin remodeling at DNA damage site and regulate the accessibility of damaged DNA to repair factors (Kapetanaki et al. 2006, Wang et al. 2006).

Identifier: R-HSA-5691006
Species: Homo sapiens
Compartment: nucleoplasm
XPC, in complex with RAD23B or RAD23A and CETN2, employs a two-stage process to recognize a distorted DNA helix. In the first stage, XPC rapidly probes dsDNA, which is promoted by a DNA repulsive action of a negatively charged beta-turn extension of XPC, located in the vicinity of the XPC DNA-binding domain. In the second stage, the DNA binding domain, consisting of two beta hairpins, binds non-hydrogen bonded bases in dsDNA (Camenisch et al. 2009). Rad4, the yeast ortholog of XPC, recognizes lesions that thermodynamically disrupt normal Watson-Crick base pairing. Rad4 inserts a beta-hairpin through the DNA duplex, causing damaged base pairs to flip out of the double helix. Rad4 associates with the undamaged strand, whereas the DNA strand that contains damaged nucleotides becomes distorted (Min and Pavletich 2007).

Binding of the XPC:RAD23:CETN2 complex to distorted DNA is enhanced in the presence of the DDB1:DDB2 complex, also known as the UV-DDB complex. The UV-DDB complex preferentially binds UV-generated lesions, such as pyrimidine-pyrimidone photodimers (6-4 PPDs) and cyclobutane pyrimidine dimers (CPDs), but also recognizes DNA with apurinic/apyrimidinic (AP) sites, and 2-3 bp mismatches (Fujiwara et al. 1999, Wittschieben et al. 2005). The DDB2 subunit of the UV-DDB complex is a WD40 repeat beta-propeller protein. The beta-propeller domain of DDB2 binds the damaged DNA strand (Scrima et al. 2008). The UV-DDB complex is part of a larger ubiquitin ligase complex that, besides DDB1 and DDB2, also contains CUL4A or CUL4B and RBX1 (Groisman et al. 2003, Sugasawa et al. 2005). In the case of 6-4 PPDs and CPDs, UV-DDB binding to damaged DNA probably precedes the binding of the XPC:RAD23:CETN2 complex. However, in the case of 6-4 PPDs, the XPC:RAD23:CETN2 complex may also recognize damaged DNA in the absence of the UV-DDB complex (Fitch et al. 2003, Moser et al. 2005, Wang et al. 2004), but the UV-DDB complex may be important for retention of DNA repair proteins at the DNA damage site (Oh et al. 2011).

The INO80 chromatin remodelling complex positively regulates GG-NER. INO80 and ACTR5 (ARP5) subunits of the INO80 complex are enriched at GG-NER sites, probably via interaction with DDB1. Chromatin relaxation by the INO80 complex at DNA damage site may be necessary for XPC recruitment (Jiang et al. 2010). In yeast, the interaction between INO80 and the orthologs of XPC and RAD23 has been reported and it was suggested that this interaction is important for the restoration of chromatin structure after GG-NER completion (Sarkar et al. 2010).

Identifier: R-HSA-6781833
Species: Homo sapiens
Compartment: nucleoplasm
Cockayne syndrome protein A (ERCC8, also known as CSA) is recruited to a stalled RNA polymerase II complex (RNA Pol II) at a site of DNA damage in an ERCC6 (CSB) dependent manner (Fousteri et al. 2006). ERCC8 is part of an ubiquitin ligase complex that, in addition to ERCC8, also contains DDB1, CUL4 (CUL4A or CUL4B) and RBX1 (Groisman et al. 2003). The COP9 signalosome complex prevents the ubiquitin ligase activity of the ERCC8:DDB1:CUL4:RBX1 at the early steps after DNA damage induction (Groisman et al. 2003, Fischer et al. 2011).

Pathway (6 results from a total of 7)

Identifier: R-HSA-8866654
Species: Homo sapiens
E3 ubiquitin ligases catalyze the transfer of an ubiquitin from an E2-ubiquitin conjugate to a target protein. Generally, ubiquitin is transferred via formation of an amide bond to a particular lysine residue of the target protein, but ubiquitylation of cysteine, serine and threonine residues in a few targeted proteins has also been demonstrated (reviewed in McDowell and Philpott 2013, Berndsen and Wolberger 2014). Based on protein homologies, families of E3 ubiquitin ligases have been identified that include RING-type ligases (reviewed in Deshaies et al. 2009, Metzger et al. 2012, Metzger et al. 2014), HECT-type ligases (reviewed in Rotin et al. 2009, Metzger et al. 2012), and RBR-type ligases (reviewed in Dove et al. 2016). A subset of the RING-type ligases participate in CULLIN-RING ligase complexes (CRLs which include SCF complexes, reviewed in Lee and Zhou 2007, Genschik et al. 2013, Skaar et al. 2013, Lee et al. 2014).
Some E3-E2 combinations catalyze mono-ubiquitination of the target protein (reviewed in Nakagawa and Nakayama 2015). Other E3-E2 combinations catalyze conjugation of further ubiquitin monomers to the initial ubiquitin, forming polyubiquitin chains. (It may also be possible for some E3-E2 combinations to preassemble polyubiquitin and transfer it as a unit to the target protein.) Ubiquitin contains several lysine (K) residues and a free alpha amino group to which further ubiquitin can be conjugated. Thus different types of polyubiquitin are possible: K11 linked polyubiquitin is observed in endoplasmic reticulum-associated degradation (ERAD), K29 linked polyubiquitin is observed in lysosomal degradation, K48 linked polyubiquitin directs target proteins to the proteasome for degradation, whereas K63 linked polyubiquitin generally acts as a scaffold to recruit other proteins in several cellular processes, notably DNA repair (reviewed in Komander et al. 2009).
Identifier: R-HSA-8852135
Species: Homo sapiens
Ubiquitin is a small, 76 amino acid residue protein that is conjugated by E3 ubiquitin ligases to other proteins in order to regulate their function or degradation (enzymatic cascade reviewed in Neutzner and Neutzner 2012, Kleiger and Mayor 2014, structures and mechanisms of conjugating enzymes reviewed in Lorenz et al. 2013). Ubiquitination of target proteins usually occurs between the C-terminal glycine residue of ubiquitin and a lysine residue of the target, although linkages with cysteine, serine, and threonine residues are also observed (reviewed in Wang et al. 2012, McDowell and Philpott 2013).
Ubiquitin must first be processed from larger precursors and then activated by formation of a thiol ester bond between ubiquitin and an E1 activating enzyme (UBA1 or UBA6) and transfer to an E2 conjugating enzyme before being transferred by an E3 ligase to a target protein. Precursor proteins containing multiple ubiquitin monomers (polyubiquitins) are produced from the UBB and UBC genes; precursors containing a single ubiquitin monomer and a ribosomal protein are produced from the UBA52 and RPS27A genes. Many proteases (deubiquitinases) may potentially process these precursors yielding monomeric ubiquitin. The proteases OTULIN and USP5 are particularly active in cleaving the polyubiquitin precursors, whereas the proteases UCHL3, USP7, and USP9X cleave the ubiquitin-ribosomal protein precursors yielding ubiquitin monomers (Grou et al. 2015). A resultant ubiquitin monomer is activated by adenylation of the C-terminal glycine followed by conjugation of the C-terminus to a cysteine residue of the E1 enzymes UBA1 or UBA6 via a thiol ester bond. The ubiquitin is then transferred from the E1 enzyme to a cysteine residue of one of several E2 enzymes (reviewed in van Wijk and Timmers 2010, Stewart et al. 2016). Through a less well characterized mechanism, E3 ubiquitin ligases then bring a target protein and the E2-ubiquitin conjugate into proximity so that the ubiquitin is transferred via formation of an amide bond to a particular lysine residue (or, in rarer cases, a thiol ester bond to a cysteine residue or an ester bond to a serine or threonine residue) of the target protein (reviewed in Berndsen and Wolberger 2014). Based on protein homologies, families of E3 ubiquitin ligases have been identified that include RING-type ligases (reviewed in Deshaies et al. 2009, Metzger et al. 2012, Metzger et al. 2014), HECT-type ligases (reviewed in Rotin et al. 2009, Metzger et al. 2012), and RBR-type ligases (reviewed in Dove et al. 2016). A subset of the RING-type ligases participate in CULLIN-RING ligase complexes (CRLs which include SCF complexes, reviewed in Lee and Zhou 2007, Genschik et al. 2013, Skaar et al. 2013, Lee et al. 2014).
Some E3-E2 combinations catalyze mono-ubiquitination of the target protein (reviewed in Nakagawa and Nakayama 2015). Other E3-E2 combinations catalyze conjugation of further ubiquitin monomers to the initial ubiquitin, forming polyubiquitin chains. (It may also be possible for some E3-E2 combinations to preassemble polyubiquitin and transfer it as a unit to the target protein.) Ubiquitin contains several lysine (K) residues and a free alpha amino group to which further ubiquitin can be conjugated. Thus different types of polyubiquitin are possible: K11 linked polyubiquitin is observed in endoplasmic reticulum-associated degradation (ERAD), K29 linked polyubiquitin is observed in lysosomal degradation, K48 linked polyubiquitin directs target proteins to the proteasome for degradation, whereas K63 linked polyubiquitin generally acts as a scaffold to recruit other proteins in several cellular processes, notably DNA repair (reviewed in Komander et al. 2009). Ubiquitination is highly regulated (reviewed in Vittal et al. 2015) and affects all cellular processes including DNA damage response (reviewed in Brown and Jackson 2015), immune signaling (reviewed in Park et al. 2014, Lutz-Nicoladoni et al. 2015), and regulation of normal and cancerous cell growth (reviewed in Skaar and Pagano 2009, Yerlikaya and Yontem 2013, Strikoudis et al. 2014).
Identifier: R-HSA-5696394
Species: Homo sapiens
Compartment: nucleoplasm
In global genome nucleotide excision repair (GG-NER), the DNA damage is recognized by two protein complexes. The first complex consists of XPC, RAD23A or RAD23B, and CETN2. This complex probes the DNA helix and recognizes damage that disrupts normal Watson-Crick base pairing, which results in binding of the XPC:RAD23:CETN2 complex to the undamaged DNA strand. The second complex is a ubiquitin ligase UV-DDB that consists of DDB2, DDB1, CUL4A or CUL4B and RBX1. The UV-DDB complex is necessary for the recognition of UV-induced DNA damage and may contribute to the retention of the XPC:RAD23:CETN2 complex at the DNA damage site. The UV-DDB complex binds the damaged DNA strand (Fitch et al. 2003, Wang et al. 2004, Moser et al. 2005, Camenisch et al. 2009, Oh et al. 2011).
Identifier: R-HSA-5696399
Species: Homo sapiens
Compartment: nucleoplasm
The DNA damage in GG-NER is recognized by the joint action of two protein complexes. The first complex is composed of XPC, RAD23A or RAD23B and CETN2. The second complex, known as the UV-DDB complex, is an ubiquitin ligase composed of DDB1, CUL4A or CUL4B, RBX1 and a GG-NER specific protein DDB2. In vitro, the UV-DDB complex is onlynecessary for GG-NER mediated repair of UV-induced pyrimidine dimers. In vivo, however, where DNA repair occurs in the chromatin context, the UV-DDB complex likely facilitates GG-NER mediated repair irrespective of the DNA damage type.
After DNA damage recognition, the TFIIH complex, together with XPA, verifies the DNA damage and unwinds the DNA helix around the damage, creating an open bubble. Two DNA endonucleases, ERCC5 (XPG) and the complex of ERCC1 and ERCC4 (XPF), excise the oligonucleotide that contains damaged base(s) from the affected DNA strand. DNA polymerases delta, epsilon and/or kappa perform DNA repair synthesis, followed by DNA ligation, thus completing GG-NER.
For a recent review, please refer to Marteijn et al. 2014.
Identifier: R-HSA-6781823
Species: Homo sapiens
Compartment: nucleoplasm
Formation of TC-NER pre-incision complex is initiated when the RNA polymerase II (RNA Pol II) complex stalls at a DNA damage site. The stalling is caused by misincorporation of a ribonucleotide opposite to a damaged base (Brueckner et al. 2007). Cockayne syndrome protein B (ERCC6, CSB) binds stalled RNA Pol II and recruits Cockayne syndrome protein A (ERCC8, CSA). ERCC8 is part of an ubiquitin ligase complex that also contains DDB1, CUL4A or CUL4B and RBX1. This complex is implicated in the regulation of TC-NER progression probably by ubiquitinating one or more factors involved in this pathway, which may include RNA Pol II and ERCC6 at the later stages of repair (Bregman et al. 1996, Fousteri et al. 2006, Groisman et al. 2006). XPA is recruited to the TC-NER site through its interaction with the TFIIH complex (Furuta et al. 2002, Ziani et al. 2014). The XAB2 complex, which probably regulates the accessibility of the DNA damage site through its RNA-DNA helicase activity, binds the TC-NER site via the interaction of its XAB2 subunit with RNA Pol II, ERCC6, ERCC8 and XPA (Nakatsu et al. 2000, Sollier et al. 2014). TCEA1 (TFIIS) is a transcription elongation factor that may facilitate backtracking of the stalled RNA Pol II, enabling access of repair proteins to the DNA damage site and promotes partial digestion of the 3' protruding end of the nascent mRNA transcript by the backtracked RNA Pol II, allowing resumption of RNA synthesis after damage removal (Donahue et al. 1994). Access to DNA damage site is also facilitated by chromatin remodelers HMGN1 (recruited to the TC-NER site through RNA Pol II and ERCC8-dependent manner) and histone acetyltransferase p300 (EP300), recruited to the TC-NER site through ERCC6-dependent manner (Birger et al. 2003, Fousteri et al. 2006). UVSSA protein interacts with ubiquitinated ERCC6 and RNA Pol II, recruiting ubiquitin protease USP7 to the TC-NER site and promoting ERCC6 stabilization (Nakazawa et al. 2012, Schwertman et al. 2012, Zhang et al. 2012, Fei and Chen 2012).
Identifier: R-HSA-5696398
Species: Homo sapiens
Compartment: nucleoplasm
Nucleotide excision repair (NER) was first described in the model organism E. coli in the early 1960s as a process whereby bulky base damage is enzymatically removed from DNA, facilitating the recovery of DNA synthesis and cell survival. Deficient NER processes have been identified from the cells of cancer-prone patients with different variants of xeroderma pigmentosum (XP), trichothiodystrophy (TTD), and Cockayne's syndrome. The XP cells exhibit an ultraviolet radiation hypersensitivity that leads to a hypermutability response to UV, offering a direct connection between deficient NER, increased mutation rate, and cancer. While the NER pathway in prokaryotes is unique, the pathway utilized in yeast and higher eukaryotes is highly conserved.
NER is involved in the repair of bulky adducts in DNA, such as UV-induced photo lesions (both 6-4 photoproducts (6-4 PPDs) and cyclobutane pyrimidine dimers (CPDs)), as well as chemical adducts formed from exposure to aflatoxin, benzopyrene and other genotoxic agents. Specific proteins have been identified that participate in base damage recognition, cleavage of the damaged strand on both sides of the lesion, and excision of the oligonucleotide bearing the lesion. Reparative DNA synthesis and ligation restore the strand to its original state.
NER consists of two related pathways called global genome nucleotide excision repair (GG-NER) and transcription-coupled nucleotide excision repair (TC-NER). The pathways differ in the way in which DNA damage is initially recognized, but the majority of the participating molecules are shared between these two branches of NER. GG-NER is transcription-independent, removing lesions from non-coding DNA strands, as well as coding DNA strands that are not being actively transcribed. TC-NER repairs damage in transcribed strands of active genes.
Several of the proteins involved in NER are key components of the basal transcription complex TFIIH. An ubiquitin ligase complex composed of DDB1, CUL4A or CUL4B and RBX1 participates in both GG-NER and TC-NER, implying an important role of ubiquitination in NER regulation. The establishment of mutant mouse models for NER genes and other DNA repair-related genes has been useful in demonstrating the associations between NER defects and cancer.
For past and recent reviews of nucleotide excision repair, please refer to Lindahl and Wood 1998, Friedberg et al. 2002, Christmann et al. 2003, Hanawalt and Spivak 2008, Marteijn et al. 2014).
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