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

Molecular weight

87 kda (Sc); 180 kDa (mammalian)

Biochemical properties


Some of the BRCT domains of TopBP1 can bind ssDNA (2)



•BRCT domains

Dpb11 -4 

Cut5/rad4 – 4 (1)

Mus101-7 (3)

topbp1-7 (4)




Sc (Dpb11)

•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

•Crb3 (19)

• 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

•Sumo (30)

•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)


Other comments


• 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)


c elegans

•replication defects (61) chromatin damage and anaphase bridges. May be affected by sumoylation.


Revised by


Last edited

14 July 08




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