ORC (Origin recognition complex)

Heterohexameric complex composed of Orc1-6. Binds to DNA and needed to assemble Mcm2-7 complex onto chromatin (also requires Cdc6 and Cdt1) (1) .

Orthologues
Molecular weight	104 kDa (ScOrc1); 71 kDa (ScOrc2); 72 kDa (ScOrc3); 61 kDa (ScOrc4); 55 kDa (ScOrc5); 50 kDa (ScOrc6) Xenopus 110, 68,64,48,43,27 for Orc1-6. Drosophila (2) (3)
Biochemical properties	Sc •DNA binding, a) ARS specific - binds primarily to A region but over B regions aswell at hi concentrations (4) b) non specific : no ATP binds ssDNA (strength as RPA) / + ATP preferentially binds ds (5) (note that DNA binding is less or not sequence specific in other eukaryotes) • Mapping subunit locations on DNA (6) (7) • ATP binding/ ATPase (required for subunit interactions?) (8) and MCM binding (9) •suggested with Cdc6 to have RF-C type (clamp loader) function in loading Mcm2-7 complex (10) •Alternative suggestion is that may have origin DNA destabilizing activity during replication initiation, analogous to DnaA (11) •Alternatively, may have origin DNA destabilizing activity during replication initiation, analogous to DnaA (10) (12) Sp •DNA binding does not require ATP, occurs via Orc4 subunit (13) • mechanism of loading of complex onto chromatin (14) (15) Dm • DNA binding specificity for negatively supercoiled vs. linear / relaxed DNA. Hyper-phosphorylation stops binding (16) Archae • DNA binding properties (17)
Motifs	AAA+ ATPase (Orc1-5) (18)
Interactions	Intersubunit interactions: Sc • orc5 and 6 can homodimerise (19) • (20) • (21) Sp (22) Mammals (23) (24) (25) (26) HsOrc235 forms a core that forms ATP-dependent interaction with Orc4. HsOrc1 shows ATP dependent interaction with Orc4,5. Orc6 does not appear to be stably associated with HsOrc1-5. Interactions with non-ORC proteins Sc • Cdc6 (27) (28) suggest aids ORC specificity (29) •Cdc7 and Sas2 (30) (genetic), •mum2 (31) ( genetic) •Screen (32) (20) •Yph1/Nop7 (33) •Noc3 (34) •Cdc28-Clb5 (35) • cdt1 (36) • hat1/2 (37) Sp •Cdc18 (38) Xl •Cdc2-cyclin A1 (39) , (40) Dm •E2f (41) controls localisation •HP1 (42) • ORC1 and 2 with DP/Rb/e2f complexes Via Rb (43) Mammals • hp1 a and b but not g (44) • ku (45) • trf2 (46) (47) (48) • hmgA1 (49) (50) • EBNA1 (50)
Modifications
Structure	Sc • em (5) Sp •AFM (bound to ARS1) (51) Dm •EM; spiral structure around DNA (11) , (52) Archael • Sulfolobus solfataricus (53) • A pernix (54) • review (55)
Cellular location and expression	Sc •Orc on chromatin all through cell cycle Xl •Orc off chromatin in mitosis. Pro/metaphase strong cytoplasmic staining. back on v fast in anaphase (56) Dm • chromatin loading patterns (57)
Other comments	Sc • Also functions in silencing (58) (59) (60) • needs ATP (hydrolysis) to bind origins but pombe doesn’t. (61) • suggested role in chromatid cohesion (62) • not needed for elongation (63) Sp • pombe orc can’t replace xenopus in extracts but big excess does inhibit replication (61) • genome wide binding (64) • role in cohesin loading? Dm • ORC binding in development (65) • amplification locus loads orc via interaction RNA polymerase 2 (66) Xl • Stably bound to DNA in Sc and Sp cell cycle but entire ORC complex dissociates from chromatin during Xenopus mitosis Mammals •ORC binds origin of bpv (67) – and orip of ebna (68) • splice variants of mouse orc 1 2 3 (69) •CHO?/xenopus If remove orc from preRC initiation can still start (70) •Orc is bound to some nuclear structure that cannot be removed by endonucleases (70) •Chromatin interaction of orc quite mobile. (71) •suggested role in telomere maintenance (46) • binding sites in rDNA (72) Archaea •Often have fewer subunits. Often have 1 protein equally related to ORC1 and cdc6 eg (73) • genome wide binding (74) •positive and megative effects on MCM binding (17) tetrahymena • RNA molecule needed for ORC function in rDNA region (75) • During replication of kinetoplast circles the origin initiating protein is activated by a change in its redox state (76)
Revised by
Last edited	9 July 09

Orc1

Synonyms
Molecular weight
Biochemical properties	Sc •ATP binding / ATPase(DNA dependent) (77) needs some contribution orc4 arg267 (8) Mammals •gal `orc1 can direct loading downstream proteins at gal site on plasmid (12)
Motifs	Sc •ATPase (77) • sir 3 homology (78) • bromo adjacent homology domain (also in sir 3) (79) often in proteins which bind acetyl lysines. If mutated chromatin affinity down (80) • cdk consensus (81)
Interactions	Sc •Sir 1 (82) (83) Direct) (84) •NatA (acetylase with role in silencing) (85) •Hbo 1 (86) • cdc6 (19) Dm •Hp1 (direct) (42) (87) •HOAP 9 (some homology to hmg) - (88) •E2f1 (89) also reports some effects rb (not necessarily direct). Mammals •HBO human acetyl transferase - (86) •myc ( in vitro) (90) •viral cyclin d homologue from hhv8 (91) • AIF-c (92) if lose interaction can’t bind to ald b origin
Modifications	Drosophila •ubiquitinated (93) •Phosphorylated (94) Xenopus •Phosphorylated (95) Mammals • ubiquitinated – (mono) Ub orc sequestered in nuclear membrane. Runs as doublet (96) (70) • Phosphorylated - M phase hyperphosphorylation by cdk2 (97) - mitotic (98) - hyperphosphorylated g2/m (96)
Structure
Cellular location and expression	Xl •released as mcm3 binds (99) Dm • degradation ORC1 occurs different stage of cell cycle to mammalian (end of M) (93) uses O box (bit like d box) (100) Mammals •Human destabilized (ie dissociates from ORC complex) in s, ub and degraded, rebinds in MG transition (70) • CHO – overexpressed degraded nascent not (is ub). Must be in cytoplasm to be degraded. role to sequester not degrade here (97) •Chromatin interaction of Orc1 and Orc4 is dynamic in cell (71)
Other comments	Sp •Not released by MNAse (101) Dm • controlled by e2f. (102) • not needed for endoreduplication (103) Mammals •In adriamycin (ds breaks) orc 1 down and off chromatin (orc2 not) (104) Plants •2 forms of orc 1 preferentially expressed proliferating or endoreduplicating. (105) Plasmodium • co-operates sir2 in telomeric silencing (106) . leishmania •Orc1 is only orc subunit (107)
Revised by
Last edited	9 July 09

Orc2

Synonyms
Molecular weight
Biochemical properties	Mammals • gal `orc2 can direct loading downstream proteins at gal site on plasmid (12)
Motifs	• cdk consensus (81) )
Interactions	Sc •Mge1( homologue E coli grpE) (108) genetic/ direct : •Oaf1, Cdc7, Cdc14, (109) • MCM2 (19) • Spp1/H3/ trimethylated H3 (110) Sp •Cdc18, Cdc2 (111)
Modifications	Sc •Phosphorylation (81) (cdc28 and clbs) migrates as doublet. cell cycle regulated; hypo in g1, hyper just after start till next g1. Sp • phosphorylation mostly cdc2 dependent some independent. Appears s and peaks g2 (112) Drosophila •Phosphorylated (94) Xenopus •Phosphorylated (95) Mammals •consistently phosphorylated (98)
Structure
Cellular location and expression	Mammals •Seems to be on chromatin at all times in human cells (113) • binds heterochromatin and hp1 in g1/s orc2 localises to centrisomes throughout the cell cycle. (44)
Other comments	Dm • Orc2 complements silencing defect of Sc mutant but not replication defect. (114) Mammals • RNAi suggests orc involved in coordinating centrisome duplication/ chromosome structure and replication (44) • Orc2 functional domains (115) • cells with low levels have defect in p53 and cdk activation (116)
Revised by
Last edited	9 July 09

Orc3

Orthologues	Latheo (117)
Molecular weight
Biochemical properties
Motifs
Protein interactions
Modifications
Structure
Cellular location and expression
Other comments
Revised by
Last edited	9 July 09

Orc4

Orthologues	SpOrp4
Molecular weight
Biochemical properties	Sp •Binds to AT rich DNA (some sequence specificity) (28) Mammals • orc4 in vitro analysis (118)
Motifs	Sp •AT hook (13)
Protein interactions	Sc • Hsp70 (119)
Modifications
Structure
Cellular location and expression
Other comments	Sp • Stays bound to DNA if extract other subunits (22) . • Determines DNA sequence specificity of entire ORC
Revised by
Last edited	9 July 09

Orc5

Synonyms
Molecular weight
Biochemical properties	•ATP binding/ATPase (DNA independent) (77)
Motifs	• ATPase (77)
Protein interactions
Modifications
Structure
Cellular location and expression
Other comments	Sp • orc5 ony needed late G1 ( not early or S) (120) • orc 5 role in cohesin loading? (121) Mammals • alternative splicing in humans (122) Plasmodium • Orc 5 characterisation (123)
Revised by
Last edited	9 July 09

Orc6

Synonyms
Molecular weight
Biochemical properties
Motifs
Interactions	Sc •cdc46 (124) •clb5 (125) • cdt1 (19) • MCM10 (19) Dm •Peanut (septin needed in cell cortex and cytokinesis (126)
Modifications	Sc •Phosphorylation; cdk consensus; migrates as doublet; phosphorylation needs cdc28 and clbs; cell cycle regulated; hypo in g1, hyper just after start till next g1 (81) . Phosphorylation in n terminus stops preRC formation Mammals • phosphorylated but no change in cell cycle (127)
Structure
Cellular location and expression	Sc • always in nucleus not at cell periphery or midbody as in other species (19) Xl •May not be required for Mcm2-7 chromatin loading in Xenopus (128) Mammals •Orc6 weakly associated with Orc1-5 complex in vertebrate cells. (127) • changes in location in cell cycle : -Interphase – nucleus. -Prophase / late mitosis reticular pattern at the cell periphery (as drosophila orc6). -Metaphase reticular structure adjacent to the chromatin. -anaphase at position that defines eventual cell division plane. -Late anaphase orc 6 reticular structures aggregated and mostly present in the mid zone. -Telophase starts to redistribute to daughters but some of it is still present in the midzone. -Also prophase to anaphase get punctate pattern in chromosomes same as centromere binding proteins, gone by telophase. (129)
Other comments	Sc • needed for multiple rounds of loading of MCMs (130) Dm • absolutely needed for ORC ATP dependent DNA binding in vitro (126) , (131) • Separate pool (50% unattached) (132) Mammals •suggested segregation role. (129) • Down regulation orc6 sensitises colorectal cancer cells to 5-FU and cisplatin treatment (133)
Revised by
Last edited	9 July 09

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