BioPAX pathway converted from "Cohesin binding to decondensed chromatin is facilitated by NIPBL:MAU2" in the Reactome database. Cohesin binding to decondensed chromatin is facilitated by NIPBL:MAU2 Cohesin binding to decondensed chromatin is facilitated by NIPBL:MAU2 Cohesin, in complex with WAPAL and PDS5 (PDS5A or PDS5B) binds decondensed chromatin in telophase (Kueng et al. 2006). This binding is facilitated by the NIPBL:MAU2 complex, also known as the 'cohesin loading complex'. NIPBL:MAU2 complex is associated with chromatin from telophase until prophase (Watrin et al. 2006) but seems to form a transient rather than stable complex with cohesin. Authored: Orlic-Milacic, M, 2012-10-02 Reviewed: Zhang, Nenggang, 2012-10-22 Reviewed: Watanabe, Yoshinori, 2012-11-20 Reviewed: Tanno, Yuji, 2012-11-20 Edited: Matthews, L, 2012-10-05 Edited: Gillespie, ME, 2012-10-05 Reactome DB_ID: 2468042 2 nucleoplasm GO 0005654 Cohesin:PDS5:WAPAL [nucleoplasm] Cohesin:PDS5:WAPAL Reactome DB_ID: 2466355 1 UniProt:Q7Z5K2 WAPL WAPL WAPAL FOE WAPL KIAA0261 FUNCTION Regulator of sister chromatid cohesion in mitosis which negatively regulates cohesin association with chromatin. Involved in both sister chromatid cohesion during interphase and sister-chromatid resolution during early stages of mitosis. Couples DNA replication to sister chromatid cohesion. Cohesion ensures that chromosome partitioning is accurate in both meiotic and mitotic cells and plays an important role in DNA repair.SUBUNIT Interacts with the cohesin complex throughout the cell cycle; interacts with both chromatin-bound and soluble pools of the complex. Interacts with RAD21; the interaction is direct. Interacts with PDS5A; the interaction is direct, cohesin-dependent and competitive with CDCA5/SORORIN. Interacts (via FGF motifs) with PDS5B; the interaction is direct. Interacts with a SMC1 protein (SMC1A or SMC1B) and SMC3.SUBUNIT (Microbial infection) Isoform 2 interacts with Epstein-Barr virus EBNA2.TISSUE SPECIFICITY Isoform 1 is highly expressed in uterine cervix tumor. Isoform 2 is widely expressed with a high level in skeletal muscle and heart.SIMILARITY Belongs to the WAPL family. Reactome http://www.reactome.org Homo sapiens NCBI Taxonomy 9606 UniProt Q7Z5K2 Chain Coordinates 1 EQUAL 1190 EQUAL Reactome DB_ID: 1641505 1 Cohesin Complex [nucleoplasm] Cohesin Complex Reactome DB_ID: 64561 1 UniProt:Q14683 SMC1A SMC1A DXS423E SMC1L1 KIAA0178 SMC1A SB1.8 SMC1 FUNCTION Involved in chromosome cohesion during cell cycle and in DNA repair. Central component of cohesin complex. The cohesin complex is required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. The cohesin complex may also play a role in spindle pole assembly during mitosis. Involved in DNA repair via its interaction with BRCA1 and its related phosphorylation by ATM, or via its phosphorylation by ATR. Works as a downstream effector both in the ATM/NBS1 branch and in the ATR/MSH2 branch of S-phase checkpoint.SUBUNIT Forms a heterodimer with SMC3 in cohesin complexes (PubMed:22628566). Cohesin complexes are composed of the SMC1 (SMC1A or SMC1B) and SMC3 heterodimer attached via their SMC hinge domain, RAD21 which link them, and one STAG protein (STAG1, STAG2 or STAG3), which interacts with RAD21 (PubMed:11076961). In germ cell cohesin complexes, SMC1A is mutually exclusive with SMC1B (By similarity). Interacts with BRCA1 (PubMed:11877377). Found in a complex with CDCA5, SMC3 and RAD21, PDS5A/SCC-112 and PDS5B/APRIN (PubMed:15837422). Interacts with NDC80 (PubMed:9295362, PubMed:10409732,). Interacts with BRAT1 (PubMed:22977523). Found in a complex containing POLE and SMC3. Interacts with RPGR, STAG3 and SYCP2 (By similarity). Found in a cohesin complex with SMC3, STAG1 and RAD21 (PubMed:22628566). The SMC1A-SMC3 heterodimer interacts with the NIPBL-MAU2 heterodimer (PubMed:22628566).DOMAIN The flexible SMC hinge domain, which separates the large intramolecular coiled coil regions, allows the heterotypic interaction with the corresponding domain of SMC3, forming a V-shaped heterodimer. The two heads of the heterodimer are then connected by different ends of the cleavable RAD21 protein, forming a ring structure (By similarity).PTM Ubiquitinated by the DCX(DCAF15) complex, leading to its degradation.PTM Phosphorylated by ATM upon ionizing radiation in a NBS1-dependent manner. Phosphorylated by ATR upon DNA methylation in a MSH2/MSH6-dependent manner. Phosphorylation of Ser-957 and Ser-966 activates it and is required for S-phase checkpoint activation.MISCELLANEOUS Mutated Cornelia de Lange cell lines display genomic instability and sensitivity to ionizing radiation and interstrand cross-linking agents.SIMILARITY Belongs to the SMC family. SMC1 subfamily. UniProt Q14683 1 EQUAL 1233 EQUAL Reactome DB_ID: 163042 1 UniProt:O60216 RAD21 RAD21 RAD21 HR21 SCC1 KIAA0078 NXP1 SUBUNIT Component of the cohesin complex, which consists of an SMC1A/B and SMC3 heterodimer core and 2 non-Smc subunits RAD21 and STAG1/SA1, STAG2/SA2 or STAG3/SA3 (PubMed:10931856, PubMed:11590136, PubMed:22628566, PubMed:25575569). Interacts (via N-terminus) with SMC1A; the interaction is direct (PubMed:12198550). The cohesin complex interacts with NUMA1 (PubMed:11590136). The cohesin complex also interacts with CDCA5, PDS5A and PDS5B; this interaction might regulate the ability of the cohesin complex to mediate sister chromatid cohesion (PubMed:15837422). The interaction with PDS5B is direct and is stimulated by STAG1/SA1 (PubMed:19696148). The cohesin complex interacts with the cohesin loading complex subunits NIPBL/Scc2 (via HEAT repeats) and MAU2/Scc4 (PubMed:22628566). The cohesin complex interacts with DDX11/ChIR1 (PubMed:17105772). Directly interacts with WAPL; this interaction is stimulated by STAG1/SA1 (PubMed:19696148). Interacts with the ISWI chromatin remodeling complex component SMARCA5; the interaction is direct (PubMed:12198550). Interacts with the NuRD complex component CHD4; the interaction is direct (PubMed:12198550).TISSUE SPECIFICITY Expressed in the gut (at protein level).DEVELOPMENTAL STAGE Regulated in a cell cycle-dependent manner: expression increases in late S phase and reaches maximum in G2 at the nucleotide level (PubMed:8812457). Not regulated during the cell cycle (at protein level) (PubMed:11073952).DOMAIN The C-terminal part associates with the head of SMC1A, while the N-terminal part binds to the head of SMC3.PTM Cleaved by separase/ESPL1 at the onset of anaphase; this cleavage is required for sister chromatid separation and cytokinesis (PubMed:11509732). Cleaved by caspase-3/CASP3 or caspase-7/CASP7 at the beginning of apoptosis (PubMed:12417729, PubMed:11875078).PTM Phosphorylated; becomes hyperphosphorylated in M phase of cell cycle. The large dissociation of cohesin from chromosome arms during prophase may be partly due to its phosphorylation by PLK1.SIMILARITY Belongs to the rad21 family. UniProt O60216 1 EQUAL 631 EQUAL Reactome DB_ID: 163016 1 UniProt:Q8WVM7 STAG1 STAG1 STAG1 SA1 SCC3 FUNCTION Component of cohesin complex, a complex required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. The cohesin complex may also play a role in spindle pole assembly during mitosis.SUBUNIT Cohesin complexes are composed of a heterodimer between a SMC1 protein (SMC1A or SMC1B) and SMC3, which are attached via their hinge domain, and RAD21 which link them at their heads, and one STAG protein (STAG1, STAG2 or STAG3). In cohesin complexes, STAG1 is mutually exclusive with STAG2 and STAG3 (PubMed:11076961). Interacts directly with RAD21 in cohesin complex (By similarity). Found in a cohesin complex with SMC1A, SMC3 and RAD21 (PubMed:22628566).PTM Phosphorylated by PLK1. The large dissociation of cohesin from chromosome arms during prophase is partly due to its phosphorylation (By similarity).SIMILARITY Belongs to the SCC3 family. UniProt Q8WVM7 1 EQUAL 1258 EQUAL Reactome DB_ID: 163009 1 UniProt:Q9UQE7 SMC3 SMC3 SMC3L1 CSPG6 SMC3 BMH BAM FUNCTION Central component of cohesin, a complex required for chromosome cohesion during the cell cycle. The cohesin complex may form a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. Cohesion is coupled to DNA replication and is involved in DNA repair. The cohesin complex also plays an important role in spindle pole assembly during mitosis and in chromosomes movement.SUBUNIT Forms a heterodimer with SMC1A or SMC1B in cohesin complexes (PubMed:22628566). Cohesin complexes are composed of the SMC1 (SMC1A or SMC1B) and SMC3 heterodimer attached via their SMC hinge domain, RAD21 which link them, and one STAG protein (STAG1, STAG2 or STAG3), which interacts with RAD21. Also found in meiosis-specific cohesin complexes (PubMed:11076961). Found in a complex with SMC1A, CDCA5 and RAD21, PDS5A/SCC-112 and PDS5B/APRIN (PubMed:15837422). Interacts with NUMA1, and forms a ternary complex with KIF3B and KIFAP3, suggesting a function in tethering the chromosomes to the spindle pole and in chromosome movement (PubMed:9506951, PubMed:11590136). Interacts with PDS5A and WAPL; regulated by SMC3 acetylation (PubMed:19907496). Interacts (via SMC hinge domain) with KIAA1328 (via N- and C-terminal domains) (PubMed:15656913). Interacts with DDX11 (PubMed:17105772). Found in a cohesin complex with SMC1A, STAG1 and RAD21 (PubMed:22628566). The SMC1A-SMC3 heterodimer interacts with the NIPBL-MAU2 heterodimer (PubMed:22628566). Interacts with MXI1, MXD3, MXD4, SYCP2, RPGR and STAG3 (By similarity). Interacts with the NuRD complex component HDAC2; the interaction is direct (PubMed:12198550).DOMAIN The flexible SMC hinge domain, which separates the large intramolecular coiled coil regions, allows the heterotypic interaction with the corresponding domain of SMC1A or SMC1B, forming a V-shaped heterodimer. The two heads of the heterodimer are then connected by different ends of the cleavable RAD21 protein, forming a ring structure (By similarity).PTM Ubiquitinated by the DCX(DCAF15) complex, leading to its degradation.PTM Phosphorylated at Ser-1083 in a SPO11-dependent manner.PTM Acetylation at Lys-105 and Lys-106 by ESCO1 is important for genome stability and S phase sister chromatid cohesion. Regulated by DSCC1, it is required for processive DNA synthesis, coupling sister chromatid cohesion establishment during S phase to DNA replication. Deacetylation by HDAC8, regulates release of the cohesin complex from chromatin.MISCELLANEOUS Mutated Cornelia de Lange cell lines display genomic instability and sensitivity to ionizing radiation and interstrand cross-linking agents.SIMILARITY Belongs to the SMC family. SMC3 subfamily.CAUTION Was originally isolated as a proteoglycan protein (explaining its name). Although not excluded, such secreted function is not clear. UniProt Q9UQE7 1 EQUAL 1217 EQUAL Reactome DB_ID: 163046 1 UniProt:Q8N3U4 STAG2 STAG2 STAG2 SA2 FUNCTION Component of cohesin complex, a complex required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. The cohesin complex may also play a role in spindle pole assembly during mitosis.SUBUNIT Interacts directly with RAD21 in cohesin complex. Cohesin complexes are composed of a heterodimer between a SMC1 protein (SMC1A or SMC1B) and SMC3, which are attached via their hinge domain, and RAD21 which link them at their heads, and one STAG protein (STAG1, STAG2 or STAG3). In cohesin complexes, STAG2 is mutually exclusive with STAG1 and STAG3.PTM Phosphorylated by PLK1. The large dissociation of cohesin from chromosome arms during prophase is partly due to its phosphorylation (By similarity).SIMILARITY Belongs to the SCC3 family.CAUTION Variants MKMS 743-Trp--Phe-1231 DEL and HPE13 1033-Arg--Phe-1231 DEL were previously described; however, the corresponding paper has been retracted as Case 1's sex was incorrectly reported invalidating the conclusions. UniProt Q8N3U4 1 EQUAL 1231 EQUAL Reactome Database ID Release 83 1641505 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1641505 Reactome R-HSA-1641505 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1641505.1 Converted from EntitySet in Reactome Reactome DB_ID: 2468044 1 PDS5 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PDS5B [nucleoplasm] PDS5A [nucleoplasm] UniProt Q9NTI5 UniProt Q29RF7 Reactome Database ID Release 83 2468042 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2468042 Reactome R-HSA-2468042 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2468042.1 Converted from EntitySet in Reactome Reactome DB_ID: 2537690 1 chromosome GO 0005694 Chromatin [chromosome] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 2470930 2 NIPBL:MAU2 [nucleoplasm] NIPBL:MAU2 Cohesin Loading Complex SCC2:SCC4 Reactome DB_ID: 1629801 1 UniProt:Q9Y6X3 MAU2 MAU2 MAU2 SCC4 KIAA0892 FUNCTION Plays an important role in the loading of the cohesin complex on to DNA. Forms a heterodimeric complex (also known as cohesin loading complex) with NIPBL/SCC2 which mediates the loading of the cohesin complex onto chromatin (PubMed:28167679, PubMed:22628566). Plays a role in sister chromatid cohesion and normal progression through prometaphase (PubMed:16802858, PubMed:16682347).SUBUNIT Heterodimerizes with MAU2/SCC2 to form the cohesin loading complex (PubMed:16682347, PubMed:16802858, PubMed:21934712, PubMed:28167679, PubMed:22628566). The NIPBL-MAU2 heterodimer interacts with the SMC1A-SMC3 heterodimer and with the cohesin complex composed of SMC1A, SMC3, RAD21 and STAG1 (PubMed:22628566).SIMILARITY Belongs to the SCC4/mau-2 family. UniProt Q9Y6X3 1 EQUAL 613 EQUAL Reactome DB_ID: 2506879 1 UniProt:Q6KC79 NIPBL NIPBL NIPBL IDN3 SCC2 FUNCTION Plays an important role in the loading of the cohesin complex on to DNA. Forms a heterodimeric complex (also known as cohesin loading complex) with MAU2/SCC4 which mediates the loading of the cohesin complex onto chromatin (PubMed:22628566, PubMed:28914604). Plays a role in cohesin loading at sites of DNA damage. Its recruitment to double-strand breaks (DSBs) sites occurs in a CBX3-, RNF8- and RNF168-dependent manner whereas its recruitment to UV irradiation-induced DNA damage sites occurs in a ATM-, ATR-, RNF8- and RNF168-dependent manner (PubMed:28167679). Along with ZNF609, promotes cortical neuron migration during brain development by regulating the transcription of crucial genes in this process. Preferentially binds promoters containing paused RNA polymerase II. Up-regulates the expression of SEMA3A, NRP1, PLXND1 and GABBR2 genes, among others (By similarity).SUBUNIT Heterodimerizes with MAU2/SCC4 to form the cohesin loading complex (PubMed:16682347, PubMed:16802858, PubMed:21934712, PubMed:28167679, PubMed:22628566). The NIPBL-MAU2 heterodimer interacts with the SMC1A-SMC3 heterodimer and with the cohesin complex composed of SMC1A, SMC3, RAD21 and STAG1 (PubMed:22628566). Interacts directly (via PxVxL motif) with CBX5 (PubMed:15882967, PubMed:20562864). Interacts with ZNF609 (via N-terminus) (By similarity). Interacts with the multiprotein complex Integrator (By similarity). Interacts (via PxVxL motif) with CBX3 (PubMed:28167679).TISSUE SPECIFICITY Widely expressed. Highly expressed in heart, skeletal muscle, fetal and adult liver, fetal and adult kidney. Expressed at intermediates level in thymus, placenta, peripheral leukocyte and small intestine. Weakly or not expressed in brain, colon, spleen and lung.DEVELOPMENTAL STAGE In embryos, it is expressed in developing limbs and later in cartilage primordia of the ulna and of various hand bones. Sites of craniofacial expression include the cartilage primordium of the basioccipital and basisphenoid skull bones and elsewhere in the head and face, including a region encompassing the mesenchyme adjacent to the cochlear canal. Also expressed in the spinal column, notochord and surface ectoderm sclerotome and what seem to be migrating myoblasts. Expressed in the developing heart in the atrial and ventricular myocardium and in the ventricular tubeculae but absent in the endocardial cushions. Also expressed in the developing esophagus, trachea and midgut loops, in the bronchi of the lung and in the tubules of the metanephros. Expression in organs and tissues not typically affected in CDL (e.g. the developing trachea, bronchi, esophagus, heart and kidney) may reflect a bias towards underreporting of more subtle aspects of the phenotype or problems that typically present later in life. Expressed in the mesenchyme surrounding the cochlear canal possibly reflecting the hearing impairment commonly found. Weakly or not expressed in embryonic brain.DOMAIN Contains one Pro-Xaa-Val-Xaa-Leu (PxVxL) motif, which is required for interaction with chromoshadow domains. This motif requires additional residues -7, -6, +4 and +5 of the central Val which contact the chromoshadow domain.DOMAIN The C-terminal region containing HEAT repeats and Pro-Xaa-Val-Xaa-Leu (PxVxL) motif are involved in the recruitment of NIPBL to sites of DNA damage.SIMILARITY Belongs to the SCC2/Nipped-B family. UniProt Q6KC79 1 EQUAL 2804 EQUAL Reactome Database ID Release 83 2470930 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2470930 Reactome R-HSA-2470930 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2470930.1 Converted from EntitySet in Reactome Reactome DB_ID: 2537688 1 Cohesin:PDS5:WAPAL:NIPBL:MAU2:Chromatin [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 83 2470935 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2470935 Reactome R-HSA-2470935 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2470935.1 16682347 Pubmed 2006 Human Scc4 is required for cohesin binding to chromatin, sister-chromatid cohesion, and mitotic progression Watrin, Erwan Schleiffer, Alexander Tanaka, Koichi Eisenhaber, Frank Nasmyth, Kim Peters, Jan-Michael Curr. Biol. 16:863-74 17113138 Pubmed 2006 Wapl controls the dynamic association of cohesin with chromatin Kueng, Stephanie Hegemann, Björn Peters, Beate H Lipp, Jesse J Schleiffer, Alexander Mechtler, Karl Peters, Jan-Michael Cell 127:955-67