BioPAX pathway converted from "Cohesin binds PDS5 and WAPAL" in the Reactome database. LEFT-TO-RIGHT Cohesin binds PDS5 and WAPAL WAPAL (WAPL) and PDS5 proteins (PDS5A and/or PDS5B) are associated with cohesin throughout most of the cell cycle (Kueng et al. 2006, Gandhi et al. 2006). FGF motifs present in the N-terminal region of WAPAL participate in WAPAL binding to PDS5 and cohesin subunits RAD21, STAG1 (SA1) and STAG2 (SA2) (Shintomi and Hirano 2009). 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 FOE WAPAL Wings apart-like protein homolog WAPL Reactome DB_ID: 2466355 nucleoplasm GENE ONTOLOGY GO:0005654 UniProt:Q7Z5K2 WAPL WAPL FOE KIAA0261 WAPAL 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. Homo sapiens NCBI Taxonomy 9606 UniProt Q7Z5K2 1 EQUAL 1190 EQUAL Reactome Database ID Release 83 2466355 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=2466355 Reactome R-HSA-2466355 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-2466355.1 Reactome http://www.reactome.org Cohesin Complex Reactome DB_ID: 1641505 SMC1A SMC1 (BAA11495) Structural maintenance of chromosome 1-like 1 protein (SMC1alpha protein) (SB1.8/DXS423E protein) (Sb1.8) Structural maintenance of chromosome 1-like 1 protein SMC1alpha protein SB1.8/DXS423E protein Sb1.8 Reactome DB_ID: 64561 UniProt:Q14683 SMC1A SMC1A DXS423E KIAA0178 SB1.8 SMC1 SMC1L1 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 Database ID Release 83 64561 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=64561 Reactome R-HSA-64561 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-64561.1 1 RAD21 Reactome DB_ID: 163042 UniProt:O60216 RAD21 RAD21 HR21 KIAA0078 NXP1 SCC1 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 Database ID Release 83 163042 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=163042 Reactome R-HSA-163042 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-163042.1 1 SA1 STAG1 Cohesin subunit SA-1 SCC3 homolog 1 Reactome DB_ID: 163016 UniProt:Q8WVM7 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 Database ID Release 83 163016 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=163016 Reactome R-HSA-163016 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-163016.1 1 SMC3 Structural maintenance of chromosomes protein 3 Reactome DB_ID: 163009 UniProt:Q9UQE7 SMC3 SMC3 BAM BMH CSPG6 SMC3L1 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 Database ID Release 83 163009 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=163009 Reactome R-HSA-163009 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-163009.1 1 SA2 STAG2 Cohesin subunit SA-2 SCC3 homolog 2 Reactome DB_ID: 163046 UniProt:Q8N3U4 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 163046 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=163046 Reactome R-HSA-163046 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-163046.1 1 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 ComplexPortal CPX-5991 additional information MI MI:0361 ComplexPortal CPX-5989 Converted from EntitySet in Reactome PDS5 PDS5A/B PDS5A/PDS5B Reactome DB_ID: 2468044 PDS5 PDS5A Sister chromatid cohesion protein PDS5 homolog A Reactome DB_ID: 2468043 UniProt:Q29RF7 PDS5A PDS5A KIAA0648 PDS5 PIG54 FUNCTION Probable regulator of sister chromatid cohesion in mitosis which may stabilize cohesin complex association with chromatin. May couple sister chromatid cohesion during mitosis to DNA replication. 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. Interacts with WAPL (via FGF motifs) or CDCA5 (via the FGF motif); the interaction is direct, cohesin-dependent and competitive. Interacts with SMC3. Interacts with TP63.TISSUE SPECIFICITY Highest level in colon. Low levels in lung, ovary, breast and kidney. Reduced level in renal tumor tissue. Isoform 2 is expressed in kidney.DEVELOPMENTAL STAGE Cell cycle-regulated with highest level in G2 phase.MISCELLANEOUS HeLa cells with a reduced level of PDS5A show a mild defect in sister chromatid cohesion. HeLa cells with a reduced level of RAD21 show reduced association of PDS5A with chromatin.SIMILARITY Belongs to the PDS5 family. UniProt Q29RF7 1 EQUAL 1337 EQUAL Reactome Database ID Release 83 2468043 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=2468043 Reactome R-HSA-2468043 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-2468043.1 AS3 PDS5B Sister chromatid cohesion protein PDS5 homolog B APRIN Reactome DB_ID: 2468051 UniProt:Q9NTI5 PDS5B PDS5B APRIN AS3 KIAA0979 FUNCTION Regulator of sister chromatid cohesion in mitosis which may stabilize cohesin complex association with chromatin. May couple sister chromatid cohesion during mitosis to DNA replication. Cohesion ensures that chromosome partitioning is accurate in both meiotic and mitotic cells and plays an important role in DNA repair. Plays a role in androgen-induced proliferative arrest in prostate cells.SUBUNIT Interacts with the cohesin complex. Interacts with RAD21; the interaction is direct. Interacts with WAPL (via FGF motifs) or CDCA5 (via the FGF motif); the interaction is direct, cohesin-dependent and competitive (Probable).TISSUE SPECIFICITY Widely expressed.INDUCTION By the synthetic androgen R1881 in prostate carcinoma cells undergoing proliferative arrest. Maximum levels occur 18-20 hours after androgen exposure.SIMILARITY Belongs to the PDS5 family. UniProt Q9NTI5 1 EQUAL 1447 EQUAL Reactome Database ID Release 83 2468051 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=2468051 Reactome R-HSA-2468051 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-2468051.1 Reactome Database ID Release 83 2468044 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=2468044 Reactome R-HSA-2468044 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-2468044.1 Cohesin:PDS5:WAPAL Reactome DB_ID: 2468042 1 1 1 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 Reactome Database ID Release 83 2468040 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=2468040 Reactome R-HSA-2468040 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-2468040.1 17112726 Pubmed 2006 Human Wapl is a cohesin-binding protein that promotes sister-chromatid resolution in mitotic prophase Gandhi, Rita Gillespie, Peter J Hirano, Tatsuya Curr. Biol. 16:2406-17 19696148 Pubmed 2009 Releasing cohesin from chromosome arms in early mitosis: opposing actions of Wapl-Pds5 and Sgo1 Shintomi, Keishi Hirano, Tatsuya Genes Dev. 23:2224-36 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