Component of Tof1(swi1/Tim)-Mrc1 (claspin)-Csm3(Swi3/Tipin) replication pausing checkpoint complex



 Sc -Csm3 /Sp-Swi3/mammals- tipin

Molecular weight

36.3 kDa (Sc)

Biochemical properties




Protein interactions


•Mcm7 (1)

•Tof1  stoichiometric / Mrc1 substoichiometric in hu block (1)

• Synthetic lethality pol a (1)

• in GINS complex (2)

• Peroxiredoxin prxd2 (oxygen scavenger) (3)



• SAP1 (needed for chromatin recruitment) (4)



• MCM (5) MCM7 (6)

• Tim (5) all through the cycle and co dependent for stability and localization (7) , (6)

• rpa (34kDa subunit) (3)

•cyclin E ( as substrate) (6)

• claspin (6)

• polymerase (6)





Cellular location and expression


•Part of replisome progression complex (2)



• levels rise throughout S (3)

• same loading kinetics as MCM7 (6)


Other comments


•Needed for RFB (8)

• 1 of 2 parallel pathways of sister chromatid cohesion (other is mrc1 ctf18 ctf8 and dcc1) (9)

• role in replication termination (10)



•Required for pausing at mating type locus (11) (12) (13)

• role in sister chromatid cohesion (14)



• needed for chk1 phosphorylation and nuclear accumulation claspin on replication stress (7)

• suggested role in stopping fork collapse (6) , (15)


Revised by


Last edited

14 April 08



1.    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.

2.    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.

3.    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.

4.    Noguchi,C. and Noguchi,E. (2007) Sap1 promotes the association of the replication fork protection complex with chromatin and is involved in the replication checkpoint in Schizosaccharomyces pombe. Genetics 175, 553-566.

5.    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.

6.    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.

7.    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.

8.    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.

9.    Xu,H., Boone,C. and Brown,G.W. (2007) Genetic dissection of parallel sister-chromatid cohesion pathways. Genetics 176, 1417-1429.

10.  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.

11.  Dalgaard,J.Z. and Klar,A.J. (2000) swi1 and swi3 perform imprinting, pausing, and termination of DNA replication in S. pombe. Cell 102, 745-751.

12.  Krings,G. and Bastia,D. (2004) swi1- and swi3-dependent and independent replication fork arrest at the ribosomal DNA of Schizosaccharomyces pombe. Proc Natl Acad Sci U S A 101, 14085-14090.

13.  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.

14.  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.

15.  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.