Required for initiation of DNA replication. Also suggested roles in repair.
These proteins are grouped as having functional equivalence however at the sequence level they have different numbers of brct domains and the C terminal half is different between yeast and higher eukaryotes. (1)
SpCut5/Rad4; Dm mus101; Xl Cut5; Hs TopBP1
87 kda (Sc); 180 kDa (mammalian)
Some of the BRCT domains of TopBP1 can bind ssDNA (2)
Cut5/rad4 – 4 (1)
•Cdc45 Synthet lethal (5)
•Dpb2 (Pol epsilon) Multicopy suppressor (6) , direct interaction pole (7) moves relative to ars fragments as pole. (6)
•Mcm10 Synthetic lethal (8)
•Sld2 (Drc1) (9) (10) Sld2 and Sld3 via BRCT domains (11) (12) (13)
•GINS Synthetic lethal (14) co dependent for loading to chromatin
• MSA1 (15)
•Drc1 (Sld2) (16) via BRCT domains
•Crb2 (17) Rad9 (18) , needs phosphorylation and –2 brct domains rad4
• srr2 (20)
•Recq4 (21) doesn’t alter chromatin loading (22)
• ATR (to activate ATR) (23) (9-1-1 probably needed for activation (24)
• ATM (23)
• topoII (4)
• rad9/pole (25)
• hpv e2 (26) (27)
• e2f - (28) suppresses e2f activity in a reporter assay. Effect stimulated by atm phosphorylation. May also be mediated by oligomerisation of topbp1 after phosphorylation by (29)
• Pml/human ub ligase (30)
• Brg/brm (31) recruits it to promoters
• C abl (32) seems to be a substrate of it. Suggested part of a feedback loop on c abl expression.
• Atr/atrip (33) suggested localisation atr to sites of damage. Atr activation k/o no effect DNA replication (Xenopus and human)
• nbs (34)
• cdc45 at G1/S but not G2/M (35)
• PARP (36)
• Miz1 (activates p21 gene in response to UV). Needed to recruit topbp1 to chromatin, to protect it from proteosomal breakdown via HUWE. Interaction antagonized by myc (37)
• cdc45 (35)
•Ub in response to uv and degraded (38)
•phosphorylated in HU needs rad3 but not cds1/chk1 (39)
• phosphorylation site in ATR interacting region. Occurs on damage stimulus, needed for chk1 activation. Probably ATM (23)
•Phosphorylation on s phase entry (25)
•Phosphorylation after DNA damage gamma/hu (40) probably via atm
•Ubiquitination- Broken down via this pathway (41)
Cellular location and expression
•Associated with chromatin with similar kinetics to Cdc45 during in vitro replication (1)
• localises brca 1. Some moves with brca1 to pcna foci on DNA damage. (maybe some differences depending on the type of damage (25) (42) . Movement on ionizing radiation needs nbs (34) moves to replication forks on hu (40)
• Some localisation to PML bodies on IR treatment (30) related to sumosylation topBP1?
• most report no PCNA localisation in normal cycle but (43) see localisation to replication forks in the absence damage also see on centromeres as brca1 and p53?
• Localise to h2ax foci in prophase 1 (44)
• maybe involved in recombination repair (45)
• stimulates mec1 kinase (46, 47) (differences with topbp1 and atr)
• involved in DNA damage pathway complementary to h3k79 modification via 9-1-1 (48)
• Needed to load cdc45 onto chromatin (49)
• suggested that binding needs pol epsilon (39)
•Needed for chromatin binding of Cdc45 and DNA polymerases (chromatin association is not dependent on Cdc45) (1)
• needed for phosphorylation rad1 and hus 1 via atr (50)
• stimulates atr kinase (33) (51)
• depletion in extracts gives decreased replication (not elongation) (52)
•Variety phenotypes of mutants: hypersensitivity to DNA damage, low chorion amplification, low heterochromatin condensation, low post replication repair (3) not sensitive to hu. Repair (53)
• Needed to load ATR/pol a/Rad1 after DNA damage, and to activate Chk1 (54)
• Loading onto chromatin in replication and repair is RPA dependent
• 3 E2f sites in the upstream of the gene (55)
• suggested to be part of checkpoint pathway activating via atm/chk (42)
• Needed for claspin to interact with chk1 on DNA damage (56)
• gene regulated by Egr-1 (57)
• reported to be needed for preIC assembly (58)
• suggested transcriptional role (59)
• mechanism of topbp1 actvation atr. ( note dbp11 does not have homology in domains required) (60)
•replication defects (61) chromatin damage and anaphase bridges. May be affected by sumoylation.
14 July 08
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28. Liu,K., Lin,F.T., Ruppert,J.M. and Lin,W.C. (2003) Regulation of E2F1 by BRCT domain-containing protein TopBP1. Mol Cell Biol 23, 3287-3304.
29. Liu,K., Paik,J.C., Wang,B., Lin,F.T. and Lin,W.C. (2006) Regulation of TopBP1 oligomerization by Akt/PKB for cell survival. EMBO J 25, 4795-4807.
30. Xu,Z.X., Timanova-Atanasova,A., Zhao,R.X. and Chang,K.S. (2003) PML colocalizes with and stabilizes the DNA damage response protein TopBP1. Mol Cell Biol23, 4247-4256.
31. Liu,K., Luo,Y., Lin,F.T. and Lin,W.C. (2004) TopBP1 recruits Brg1/Brm to repress E2F1-induced apoptosis, a novel pRb-independent and E2F1-specific control for cell survival. Genes Dev 18, 673-686.
32. Zeng,L., Hu,Y. and Li,B. (2005) Identification of TopBP1 as a c-Abl-interacting protein and a repressor for c-Abl expression. J Biol Chem 280, 29374-29380.
33. Kumagai,A., Lee,J., Yoo,H.Y. and Dunphy,W.G. (2006) TopBP1 activates the ATR-ATRIP complex. Cell 124, 943-955.
34. Morishima,K., Sakamoto,S., Kobayashi,J., Izumi,H., Suda,T., Matsumoto,Y., Tauchi,H., Ide,H., Komatsu,K. and Matsuura,S. (2007) TopBP1 associates with NBS1 and is involved in homologous recombination repair. Biochem Biophys Res Commun 362, 872-879.
35. Schmidt,U., Wollmann,Y., Franke,C., Grosse,F., Saluz,H.P. and Hanel,F. (2008) Characterization of the interaction between the human DNA topoisomerase IIbeta-binding protein 1 (TopBP1) and the cell division cycle 45 (Cdc45) protein. Biochem J 409, 169-177.
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37. Herold,S., Hock,A., Herkert,B., Berns,K., Mullenders,J., Beijersbergen,R., Bernards,R. and Eilers,M. (2008) Miz1 and HectH9 regulate the stability of the checkpoint protein, TopBP1. EMBO J 27, 2851-2861.
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40. Yamane,K., Wu,X. and Chen,J. (2002) A DNA damage-regulated BRCT-containing protein, TopBP1, is required for cell survival. Mol Cell Biol 22, 555-566.
41. Zhang,D., Zaugg,K., Mak,T.W. and Elledge,S.J. (2006) A role for the deubiquitinating enzyme USP28 in control of the DNA-damage response. Cell 126, 529-542.
42. Kim,J.E., McAvoy,S.A., Smith,D.I. and Chen,J. (2005) Human TopBP1 ensures genome integrity during normal S phase. Mol Cell Biol 25, 10907-10915.
43. Reini,K., Uitto,L., Perera,D., Moens,P.B., Freire,R. and Syvaoja,J.E. (2004) TopBP1 localises to centrosomes in mitosis and to chromosome cores in meiosis. Chromosoma 112, 323-330.
44. Perera,D., Perez-Hidalgo,L., Moens,P.B., Reini,K., Lakin,N., Syvaoja,J.E., San-Segundo,P.A. and Freire,R. (2004) TopBP1 and ATR colocalization at meiotic chromosomes: role of TopBP1/Cut5 in the meiotic recombination checkpoint. Mol Biol Cell 15, 1568-1579.
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55. Yoshida,K. and Inoue,I. (2004) Expression of MCM10 and TopBP1 is regulated by cell proliferation and UV irradiation via the E2F transcription factor. Oncogene 23, 6250-6260.
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57. Usskilat,C., Skerka,C., Saluz,H.P. and Hanel,F. (2006) The transcription factor Egr-1 is a regulator of the human TopBP1 gene. Gene 380, 144-150.
58. Jeon,Y., Lee,K.Y., Ko,M.J., Lee,Y.S., Kang,S. and Hwang,D.S. (2007) Human TopBP1 participates in cyclin E/CDK2 activation and preinitiation complex assembly during G1/S transition. J Biol Chem 282, 14882-14890.
59. Wright,R.H., Dornan,E.S., Donaldson,M.M. and Morgan,I.M. (2006) TopBP1 contains a transcriptional activation domain suppressed by two adjacent BRCT domains. Biochem J 400, 573-582.
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