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

 

Motifs

 

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)

 

 

Modifications

 

Structure

 

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

 

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.