Disease relevance of TOPBP1

• Although E2F1 was stabilized by ultraviolet (UV) irradiation, the mRNA expression level of TopBP1 was suppressed in HCT116 human diploid colon cancer cells [1].
• Some of these alterations suggest mechanisms by which HGF/SF may exert its protective activity, e.g., up-regulation of polycystic kidney disease-1 (a survival-promoting component of cadherin-catenin complexes), down-regulation of 51C (an inositol polyphosphate-5-phosphatase), and down-regulation of TOPBP1 (a topoisomerase IIB binding protein) [2].
• Based on its biological significance, we reasoned that TopBP1 is a plausible susceptibility gene for hereditary breast and/or ovarian cancer and therefore screened affected index cases from 125 Finnish cancer families for germline changes by conformation sensitive gel electrophoresis (CSGE) [3].
• TopBP1 has eight BRCT [BRCA1 (breast-cancer susceptibility gene 1) C-terminus] domains and is involved in initiating DNA replication, and DNA damage checkpoint signalling and repair [4].

High impact information on TOPBP1

• They report that a physical interaction between ATR and a distinct domain of TopBP1 greatly enhances ATR kinase activity [5].
• TopBP1, the vertebrate homolog of yeast Cut5/Dbp11, has dual roles in initiation of DNA replication and regulation of checkpoint responses [6].
• Interestingly, TopBP1 is induced by E2F and interacts with E2F1 during G1/S transition [7].
• TopBP1 (DNA topoisomerase IIbeta binding protein I) contains multiple BRCT domains and is involved in replication and the DNA damage checkpoint [7].
• Thus, TopBP1 functions as a critical modulator and serves as a negative feedback regulator of E2F1 by inhibiting E2F1-dependent apoptosis during G1/S transition as well as DNA damage to promote cell survival [7].

Biological context of TOPBP1

• TopBP1 contains eight BRCT (BRCA1 carboxyl-terminal) motifs and upon DNA damage is recruited to stalled replication forks, where it participates in a DNA damage checkpoint [8].
• Through this interaction, TopBP1 repressed multiple activities of E2F1, including transcriptional activity, induction of S-phase entry, and apoptosis [8].
• Our data suggest a model in which UV irradiation-induced DNA damage depends, at least in part, on the accumulation of the E2F4 transcription factor on the MCM10 and TopBP1 promoters, which results in suppression of DNA replication [1].
• Furthermore, Xenopus egg extracts containing a version of TopBP1 with an inactivating point mutation in the ATR-activating domain are defective in checkpoint regulation [6].
• Phosphorylation by Akt induces oligomerization of TopBP1 through its seventh and eighth BRCT domains [9].

Associations of TOPBP1 with chemical compounds

• Both PML and TopBP1 colocalized with the IR-induced bromodeoxyuridine single-stranded DNA foci [10].
• All-trans-retinoic acid induced reorganization of the PML nuclear body (NB) and reappearance of the IR-induced TopBP1 foci [10].
• Indeed, we have shown that human TopBP1 participates in the activation of replication checkpoint and DNA damage checkpoints, following hydroxyurea treatment and ionizing radiation [11].

Physical interactions of TOPBP1

• A yeast two-hybrid screen showed that DNA topoisomerase IIbeta-binding protein 1 (TopBP1) interacted with hHYD [12].
• PML colocalizes with and stabilizes the DNA damage response protein TopBP1 [10].
• Furthermore, deletion of the E2F transcription factor binding sites or mutation of the Egr-1 transcription factor binding sites lead to reduced stimulation of the TopBP1 promoter by Egr-1 [13].
• TopBP1 (topoisomerase IIbeta binding protein 1) displays sequence homology as well as functional similarities with BRCA1, and the two proteins have been suggested to function partly in the same cellular processes [3].

Co-localisations of TOPBP1

• We show that TopBP1 tightly colocalizes with ATR in distinct nuclear subcompartments generated by DNA damage [14].

Regulatory relationships of TOPBP1

• Together, our findings demonstrate that PML regulates TopBP1 functions by association and stabilization of the protein in response to IR-induced DNA damage [10].
• Finally, we show that TopBP1 is required for the DNA damage-induced interaction between Claspin and Chk1 [14].

Other interactions of TOPBP1

• These results demonstrated that hHYD coordinated TopBP1 in the DNA damage response [12].
• Regulation of E2F1 by BRCT domain-containing protein TopBP1 [8].
• Inhibition of PML expression by siRNA is associated with a significant decreased in TopBP1 expression [10].
• In this study, we showed that the transcription of human MCM10 and TopBP1 is activated by transcription factors E2F1-3, but not by factors E2F4-7 [1].
• However, ATM-dependent phosphorylation of TopBP1 does not appear to be required for focus formation following DNA damage [15].

References