TOF1/YNL273W Summary Help

Standard Name TOF1 1
Systematic Name YNL273W
Feature Type ORF, Verified
Description Subunit of a replication-pausing checkpoint complex; Tof1p-Mrc1p-Csm3p acts at the stalled replication fork to promote sister chromatid cohesion after DNA damage, facilitating gap repair of damaged DNA; interacts with the MCM helicase; relocalizes to the cytosol in response to hypoxia (2, 3, 4, 5, 6, 7 and see Summary Paragraph)
Name Description TOpoisomerase I-interacting Factor 1
Chromosomal Location
ChrXIV:122883 to 126599 | ORF Map | GBrowse
Gbrowse
Gene Ontology Annotations All TOF1 GO evidence and references
  View Computational GO annotations for TOF1
Molecular Function
Manually curated
Biological Process
Manually curated
Cellular Component
Manually curated
Regulators 14 genes
Resources
Classical genetics
null
Large-scale survey
null
Resources
402 total interaction(s) for 205 unique genes/features.
Physical Interactions
  • Affinity Capture-MS: 21
  • Affinity Capture-RNA: 1
  • Affinity Capture-Western: 16
  • Co-localization: 1
  • Two-hybrid: 5

Genetic Interactions
  • Dosage Growth Defect: 1
  • Dosage Lethality: 1
  • Negative Genetic: 141
  • Phenotypic Enhancement: 11
  • Phenotypic Suppression: 6
  • Positive Genetic: 10
  • Synthetic Growth Defect: 119
  • Synthetic Lethality: 65
  • Synthetic Rescue: 4

Resources
Expression Summary
histogram
Resources
Length (a.a.) 1,238
Molecular Weight (Da) 141,119
Isoelectric Point (pI) 5.97
Localization
Phosphorylation PhosphoGRID | PhosphoPep Database
Structure
Homologs
sequence information
ChrXIV:122883 to 126599 | ORF Map | GBrowse
SGD ORF map
Last Update Coordinates: 2005-11-07 | Sequence: 1996-07-31
Subfeature details
Relative
Coordinates
Chromosomal
Coordinates
Most Recent Updates
Coordinates Sequence
CDS 1..3717 122883..126599 2005-11-07 1996-07-31
Retrieve sequences
Analyze Sequence
S288C only
S288C vs. other species
S288C vs. other strains
Resources
External Links All Associated Seq | Entrez Gene | Entrez RefSeq Protein | MIPS | Search all NCBI (Entrez) | UniProtKB
Primary SGDIDS000005217
SUMMARY PARAGRAPH for TOF1

Tof1p (topoisomerase I interacting factor) is a checkpoint-mediator protein that regulates DNA damage responses during S phase (8). Tof1p forms a replication-pausing mediator complex with Mrc1p and Csm3p that associates with DNA replication forks (3, 4, 9). Tof1p and Csm3p are specifically required for the association of Mrc1p with moving replication forks (9). This heterotrimeric assembly forms a stable pausing structure that serves to anchor subsequent DNA repair events (3). The Tof1/Mrc1/Csm3 checkpoint complex interacts directly with the MCM helicase during both replication fork progression and when the replication fork is stalled, and limits progression of the replisome when nucleotides are depleted (6, 10). Both Tof1p and Mrc1p are required for the proper arrest and stabilization of replication forks in the presence of hydroxyurea (3, 9). They also regulate the normal process of chromosome replication and mediate the activation of the Rad53p kinase in response to replication stress (11, 12). Tof1p and Csm3p positively control recombination provoked by polar fork arrest, and negatively control recombination provoked by transcription (13). Tof1p, Mrc1p, and Csm3p inhibit DNA repeat instability, and are required to counteract replication stalling and facilitate replication fork progression through unstable DNA repeats, which are responsible for chromosomal fragility and several hereditary disorders in humans (14, 15, 16). Tof1p and Csm3p together counteract the Rrm3p helicase to control replication termination (17).

tof1 null mutants grow normally and have normal levels of topoisomerase I activity (1), but are sensitive to UV and to hydroxyurea (8), and exhibit defects in sister chromatid cohesion (4, 5, 18). Loss of Tof1p also elevates mutation rates at DNA repeats, which are implicated in chromosome fragility and numerous hereditary disorders in humans (19), and reduces the rate of progression of DNA replication forks (12).

Homologs of TOF1 have been identified in fission yeast, Xenopus, and mammals (20, 21, 22, 23).

Last updated: 2010-06-24 Contact SGD

References cited on this page View Complete Literature Guide for TOF1
1) Park H and Sternglanz R  (1999) Identification and characterization of the genes for two topoisomerase I-interacting proteins from Saccharomyces cerevisiae. Yeast 15(1):35-41
2) Osborn AJ and Elledge SJ  (2003) Mrc1 is a replication fork component whose phosphorylation in response to DNA replication stress activates Rad53. Genes Dev 17(14):1755-67
3) Katou Y, et al.  (2003) S-phase checkpoint proteins Tof1 and Mrc1 form a stable replication-pausing complex. Nature 424(6952):1078-83
4) Mayer ML, et al.  (2004) Identification of protein complexes required for efficient sister chromatid cohesion. Mol Biol Cell 15(4):1736-45
5) Xu H, et al.  (2004) Mrc1 is required for sister chromatid cohesion to aid in recombination repair of spontaneous damage. Mol Cell Biol 24(16):7082-90
6) Nedelcheva MN, et al.  (2005) Uncoupling of unwinding from DNA synthesis implies regulation of MCM helicase by Tof1/Mrc1/Csm3 checkpoint complex. J Mol Biol 347(3):509-21
7) Ghosh Dastidar R, et al.  (2012) The nuclear localization of SWI/SNF proteins is subjected to oxygen regulation. Cell Biosci 2(1):30
8) Foss EJ  (2001) Tof1p regulates DNA damage responses during S phase in Saccharomyces cerevisiae. Genetics 157(2):567-77
9) Bando M, et al.  (2009) Csm3, Tof1, and Mrc1 form a heterotrimeric mediator complex that associates with DNA replication forks. J Biol Chem 284(49):34355-65
10) Calzada A, et al.  (2005) Molecular anatomy and regulation of a stable replisome at a paused eukaryotic DNA replication fork. Genes Dev 19(16):1905-19
11) Tourriere H, et al.  (2005) Mrc1 and Tof1 promote replication fork progression and recovery independently of Rad53. Mol Cell 19(5):699-706
12) Hodgson B, et al.  (2007) Mrc1 and Tof1 Regulate DNA Replication Forks in Different Ways during Normal S Phase. Mol Biol Cell 18(10):3894-902
13) Mohanty BK, et al.  (2009) Contrasting roles of checkpoint proteins as recombination modulators at Fob1-Ter complexes with or without fork arrest. Eukaryot Cell 8(4):487-95
14) Razidlo DF and Lahue RS  (2008) Mrc1, Tof1 and Csm3 inhibit CAG.CTG repeat instability by at least two mechanisms. DNA Repair (Amst) 7(4):633-40
15) Voineagu I, et al.  (2008) Replication stalling at unstable inverted repeats: interplay between DNA hairpins and fork stabilizing proteins. Proc Natl Acad Sci U S A 105(29):9936-41
16) Voineagu I, et al.  (2009) Replisome stalling and stabilization at CGG repeats, which are responsible for chromosomal fragility. Nat Struct Mol Biol 16(2):226-8
17) Mohanty BK, et al.  (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(4):897-902
18) Xu H, et al.  (2007) Genetic dissection of parallel sister-chromatid cohesion pathways. Genetics 176(3):1417-29
19) Shishkin AA, et al.  (2009) Large-scale expansions of Friedreich's ataxia GAA repeats in yeast. Mol Cell 35(1):82-92
20) Noguchi E, et al.  (2003) Swi1 prevents replication fork collapse and controls checkpoint kinase Cds1. Mol Cell Biol 23(21):7861-74
21) Matsumoto S, et al.  (2005) Hsk1-Dfp1/Him1, the Cdc7-Dbf4 kinase in Schizosaccharomyces pombe, associates with Swi1, a component of the replication fork protection complex. J Biol Chem 280(52):42536-42
22) Gotter AL, et al.  (2007) Mammalian TIMELESS and Tipin are evolutionarily conserved replication fork-associated factors. J Mol Biol 366(1):36-52
23) Tanaka H, et al.  (2009) Replisome progression complex links DNA replication to sister chromatid cohesion in Xenopus egg extracts. Genes Cells 14(8):949-63