Tof1/Swi1/Tipin
Component of Tof1(swi1/Tim)-Mrc1 (claspin)-Csm3(Swi3/Tipin) replication pausing checkpoint complex. Probably moves with replication forks. May maintain integrity of stalled replication forks.
Synonyms |
Sc-Tof1/Sp-Swi1/mammals - tipin |
Molecular weight |
141 kDa (Sc) |
Biochemical properties |
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Motifs |
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Protein interactions |
Sc •DNA topoisomerase I (1) • Cdc45 (2) (3) – tethers to stalled forks? • Mcm6 (3?) (4) • Csm3 (stoichiometric) /mrc1 (sub-stoichiometric) (4) in hu block • Synthetic lethality pola (4) (suggested linkage mcm complex and polymerase) • GINS complex (5) • Peroxiredoxin prxd2 (oxygen scavenger) (6)
Dm • per (7) • atr/atrip (7) •chk1 (7)
Mammals •Tipin (8) • claspin (s phase dependent) (6) •MCM2 (phosphorylated)/ pol delta and epsilon all at G1/S and don’t need tipin (6) •ATRIP/CHK1 in HU (6) •clock proteins cry1 and 2 (6)
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Modifications |
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Structure |
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Cellular location and expression |
Sc •Binds to origins and moves away with BrdU incorporation (2) (3) loads independently of Mrc1
Mammals • levels rise thoughout S (6) • same loading kinetics as MCM7 (9) |
Other comments |
Sc •Mutants give partial activation checkpoint in the presence genotoxic drugs , defective fork movement in normal cell cycle and faulty pausing in tRNA genes (10) also centromeres (mrc not beeded here) (11) •Present at blocked replication forks (12) (13) • role in replication termination (14) • 1 of 2 parallel pathways of sister chromatid cohesion (other is mrc1 ctf18 ctf8 and dcc1) (13)
Sp •Faulty pausing RFB in pombe (15) • role in sister chromatid cohesion (16)
Mammals • needed for chk1 phosphorylation and nuclear accumulation claspin on replication stress (17) •role in intra S checkpoint (18) |
Revised by |
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Last edited |
14 April 08 |
1. Park,H. and Sternglanz,R. (1999) Identification and characterization of the genes for two topoisomerase I-interacting proteins from Saccharomyces cerevisiae. Yeast 15, 35-41.
2. Katou,Y., Kanoh,Y., Bando,M., Noguchi,H., Tanaka,H., Ashikari,T., Sugimoto,K. and Shirahige,K. (2003) S-phase checkpoint proteins Tof1 and Mrc1 form a stable replication-pausing complex. Nature 424, 1078-1083.
3. Zegerman,P. and Diffley,J.F. (2003) Lessons in how to hold a fork. Nat Struct Biol 10, 778-779.
4. Nedelcheva,M.N., Roguev,A., Dolapchiev,L.B., Shevchenko,A., Taskov,H.B., Shevchenko,A., Stewart,A.F. and Stoynov,S.S. (2005) Uncoupling of unwinding from DNA synthesis implies regulation of MCM helicase by Tof1/Mrc1/Csm3 checkpoint complex. J Mol Biol 347, 509-521.
5. Gambus,A., Jones,R.C., Sanchez-Diaz,A., Kanemaki,M., van Deursen,F., Edmondson,R.D. and Labib,K. (2006) GINS maintains association of Cdc45 with MCM in replisome progression complexes at eukaryotic DNA replication forks. Nat Cell Biol 8, 358-366.
6. Gotter,A.L., Suppa,C. and Emanuel,B.S. (2007) Mammalian TIMELESS and Tipin are evolutionarily conserved replication fork-associated factors. J Mol Biol 366, 36-52.
7. Hunt,T. and Sassone-Corsi,P. (2007) Riding tandem: circadian clocks and the cell cycle. Cell 129, 461-464.
8. Chou,D.M. and Elledge,S.J. (2006) Tipin and Timeless form a mutually protective complex required for genotoxic stress resistance and checkpoint function. Proc Natl Acad Sci U S A 103, 18143-18147.
9. Errico,A., Costanzo,V. and Hunt,T. (2007) Tipin is required for stalled replication forks to resume DNA replication after removal of aphidicolin in Xenopus egg extracts. Proc Natl Acad Sci U S A 104, 14929-14934.
10. Tourriere,H., Versini,G., Cordon-Preciado,V., Alabert,C. and Pasero,P. (2005) Mrc1 and Tof1 promote replication fork progression and recovery independently of Rad53. Mol Cell 19, 699-706.
11. Hodgson,B., Calzada,A. and Labib,K. (2007) Mrc1 and Tof1 regulate DNA replication forks in different ways during normal S phase. Mol Biol Cell 18, 3894-3902.
12. Calzada,A., Hodgson,B., Kanemaki,M., Bueno,A. and Labib,K. (2005) Molecular anatomy and regulation of a stable replisome at a paused eukaryotic DNA replication fork. Genes Dev 19, 1905-1919.
13. Xu,H., Boone,C. and Brown,G.W. (2007) Genetic dissection of parallel sister-chromatid cohesion pathways. Genetics 176, 1417-1429.
14. Mohanty,B.K., Bairwa,N.K. and Bastia,D. (2006) The Tof1p-Csm3p protein complex counteracts the Rrm3p helicase to control replication termination of Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 103, 897-902.
15. Nedelcheva-Veleva,M.N., Krastev,D.B. and Stoynov,S.S. (2006) Coordination of DNA synthesis and replicative unwinding by the S-phase checkpoint pathways. Nucleic Acids Res 34, 4138-4146.
16. Ansbach,A.B., Noguchi,C., Klansek,I.W., Heidlebaugh,M., Nakamura,T.M. and Noguchi,E. (2008) RFCCtf18 and the Swi1-Swi3 Complex Function in Separate and Redundant Pathways Required for the Stabilization of Replication Forks to Facilitate Sister Chromatid Cohesion in Schizosaccharomyces pombe. Mol Biol Cell 19, 595-607.
17. Yoshizawa-Sugata,N. and Masai,H. (2007) Human Tim/Timeless-interacting protein, Tipin, is required for efficient progression of S phase and DNA replication checkpoint. J Biol Chem 282, 2729-2740.
18. Unsal-Kacmaz,K., Chastain,P.D., Qu,P.P., Minoo,P., Cordeiro-Stone,M., Sancar,A. and Kaufmann,W.K. (2007) The human Tim/Tipin complex coordinates an Intra-S checkpoint response to UV that slows replication fork displacement. Mol Cell Biol 27, 3131-3142.