Selected-GenAtlas references SOURCE GeneCards NCBI Gene Swiss-Prot Ensembl
HGNC UniGene Nucleotide OMIM UCSC
Home Page
Symbol TOPBP1 contributors: mct/ - updated : 29-04-2014
HGNC name topoisomerase (DNA) II binding protein 1
HGNC id 17008
  • an additional cryptic BRCT domain (BRCT0) at the extreme N terminus
  • an auto-ADP-ribosylation site
  • several chromatin modification domains
  • eight other BRCT domains, and BRCT domains 45 interacted with TP53BP1 and recruitment of TOPBP1 to sites of DNA DSBs in G1 was dependent on TP53BP1
  • a phosphorylated SQ/TQ site within the ATR activation domain that enhance its ability to activate ATR/ATRIP complex
  • two C-terminal nuclear localization signals, a BRCA1 C-terminal motifs, AAs 1259 to 1420 in the TOPBP1 C-terminal region (TBPCtR) are involved in localization of TOPBP1 to the mitotic centrosomes
  • eight BRCT [BRCA1 (breast-cancer susceptibility gene 1) C-terminus] domains
  • secondary structure
  • triple-BRCT domain structure
    interspecies homolog to drosophila mus101
    ortholog to S. cerevisiae BRCT repeat protein Dpb11
    homolog to murine Topbp1 (77,09 pc)
    CATEGORY regulatory , DNA associated
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytoskeleton,microtubule,mitotic spindle
  • colocalizes with TP53BP1 at sites of DNA double-strand breaks (DSBs), but only in the G1-phase of the cell cycle
  • in prometaphase, metaphase, and anaphase, localizes to the mitotic centrosomes, which function as spindle-poles for the bipolar separation of sister chromatids, and localization to the mitotic centrosomes is necessary for proper mitotic progression
  • basic FUNCTION
  • required for DNA replication
  • playing a role in the rescue of stalled replication forks and checkpoint control
  • essential activator of the ATR kinase
  • recruiting the SWI/SNF chromatin remodeling complex to E2F1-responsive promoters
  • down-regulating E2F1 activity
  • inhibiting E2F1-dependent apoptosis during G1/S transition and after DNA damage
  • required for G(1) to S progression
  • activating ATR which is a crucial step in the initiation of ATR-dependent signaling processes
  • implicated in DNA damage response
  • could repress the expression of ABL1 at both mRNA and protein levels
  • involved in initiating DNA replication, and DNA damage checkpoint signalling and repair
  • involved in the formation of the initiation complex of replication in cells and is required for the recruitment of CDC45 to origins of DNA replication
  • plays a critical role in the control of DNA replication checkpoint
  • with BRIP1, are required for ATR-dependent phosphorylation events in response to replication stress
  • has important roles in both DNA replication and checkpoint regulation
  • essential for normal G(1)/S transition, but a pathological level of TOPBP1 in cancer may perturb TP53 function and contribute to an aggressive tumor behavior
  • crucial role in actively repressing TP53
  • collaborate in the Cdk2-mediated loading of CDC45 onto replication origins
  • plays a critical role in the control of DNA replication checkpoint
  • TOPBP1 and BRIP1 are required for ATR-dependent phosphorylation events in response to replication stress
  • checkpoint protein that colocalizes with ATR at sites of DNA replication stress
  • scaffold protein that coordinates activation of the DNA-damage-checkpoint response by coupling binding of the 9-1-1 checkpoint clamp at sites of ssDNA
  • may mediate the checkpoint function of TP53BP1 in G1
  • emergence of TOPBP1 as a key regulator in the DNA replication checkpoint pathway is underscored by its multiple roles contributing to the activation of ATR
  • its role as an integrator of diverse signals that control the replication stress response critically depends on its nine BRCT domains that dictate diverse molecular interactions
  • plays important roles in chromosome replication, DNA damage response, and other cellular regulatory functions, and is essential for cell proliferation during early embryogenesis
  • triggers cellular senescence in human primary cells
  • plays important roles in DNA damage response, DNA replication, and other cellular regulatory functions during the interphase
  • required for the initiation of DNA replication and for DNA repair and damage signalling
  • plays multiple roles in the regulation of DNA damage checkpoint signaling
  • WDR18 is a bona fide checkpoint protein and works together with TOPBP1 to promote DNA damage checkpoint signaling
  • NBN and TOPBP1 have the potential to activate ATR independently, although both are required for functional activation of ATR
  • TICRR like TOPBP1, is a dual replication/checkpoint protein that directly participates in ATR-mediated checkpoint signaling
  • controls BLM protein level to maintain genome stability
  • role in HR, with potential clinical implications for cancer treatment
  • CELLULAR PROCESS cell cycle, checkpoint
    nucleotide, replication
    nucleotide, repair
    a component
  • binding double-stranded DNA breaks and nicks
  • binding single-stranded DNA
  • RNA
    small molecule
  • EDD
  • E2F1
  • PML
  • RAD9A
  • POLE
  • TOP2B
  • ABL1-interacting protein and repressor for ABL1 expression
  • interacting with ZBTB17 (ZBTB17 is required for the binding of a fraction of TOPBP1 to chromatin and to protect TOPBP1 from proteasomal degradation)
  • interacting with CDC45 (required for chromatin loading of the replication protein CDC45)
  • functions as a general activator of ATR
  • specific interaction between TOPBP1 and BRIP1, a DNA helicase involved in the repair of DNA crosslinks
  • specific interaction between TOPBP1 and BACH1/FANCJ, a DNA helicase involved in the repair of DNA crosslinks
  • interaction with FANCM (FANCM is required for efficient activation of ATR by promoting TOPBP1 loading on chromatin)
  • interacting with TICRR (Treslin associates with TOPBP1 in a Cdk2-dependent manner)
  • RAD9A interacts with TOPBP1 and is required for proper localization of topoisomerase II-binding protein 1 (TOPBP1) in response to DNA damage
  • binds one of its critical partners in the DNA damage response, BRIP1 (crucial for the response to DNA replication stress)
  • WDR18 associates with the C-terminus of TOPBP1
  • specific interaction between TOPBP1 and BLM that is phosphorylation and cell-cycle dependent
  • TOPBP1 physically binds PLK1 and promotes PLK1 kinase-mediated phosphorylation of RAD51 at serine 14, a modification required for RAD51 recruitment to chromatin
  • cell & other
    induced by E2F1 and interferon
    repressed by ultraviolet (UV) irradiation
    Other up-regulated during the S phase of the cell cycle
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional       loss of function
    upregulates TP53 target genes involved in cell cycle arrest and apoptosis and enhances DNA damage-induced apoptosis
    up-regulates TP53 target genes involved in cell cycle arrest and apoptosis, thereby inducing DNA damage-induced apoptosis because interaction of TOPBP1 with the TP53 DNA binding domain inhibits the binding of TP53 to the promoters
    Susceptibility to familial breast and ovarian cancer
    Variant & Polymorphism other polymorphisms increasing the risk of breast and ovarian cancer
    Candidate gene
    Therapy target