| comment |
-
FUNCTION Scaffold protein that acts as a key protein-protein adapter in DNA replication and DNA repair (PubMed:10498869, PubMed:11395493, PubMed:11714696, PubMed:17575048, PubMed:20545769, PubMed:21777809, PubMed:26811421, PubMed:30898438, PubMed:31135337, PubMed:33592542, PubMed:35597237, PubMed:37674080). Composed of multiple BRCT domains, which specifically recognize and bind phosphorylated proteins, bringing proteins together into functional combinations (PubMed:17575048, PubMed:20545769, PubMed:21777809, PubMed:26811421, PubMed:30898438, PubMed:31135337, PubMed:35597237, PubMed:37674080). Required for DNA replication initiation but not for the formation of pre-replicative complexes or the elongation stages (By similarity). Necessary for the loading of replication factors onto chromatin, including GMNC, CDC45, DNA polymerases and components of the GINS complex (By similarity). Plays a central role in DNA repair by bridging proteins and promoting recruitment of proteins to DNA damage sites (PubMed:30898438, PubMed:35597237, PubMed:37674080). Involved in double-strand break (DSB) repair via homologous recombination in S-phase by promoting the exchange between the DNA replication factor A (RPA) complex and RAD51 (PubMed:26811421, PubMed:35597237). Mechanistically, TOPBP1 is recruited to DNA damage sites in S-phase via interaction with phosphorylated HTATSF1, and promotes the loading of RAD51, thereby facilitating RAD51 nucleofilaments formation and RPA displacement, followed by homologous recombination (PubMed:35597237). Involved in microhomology-mediated end-joining (MMEJ) DNA repair by promoting recruitment of polymerase theta (POLQ) to DNA damage sites during mitosis (PubMed:37674080). MMEJ is an alternative non-homologous end-joining (NHEJ) machinery that takes place during mitosis to repair DSBs in DNA that originate in S-phase (PubMed:37674080). Recognizes and binds POLQ phosphorylated by PLK1, enabling its recruitment to DSBs for subsequent repair (PubMed:37674080). Involved in G1 DNA damage checkpoint by acting as a molecular adapter that couples TP53BP1 and the 9-1-1 complex (PubMed:31135337). In response to DNA damage, triggers the recruitment of checkpoint signaling proteins on chromatin, which activate the CHEK1 signaling pathway and block S-phase progression (PubMed:16530042, PubMed:21777809). Acts as an activator of the kinase activity of ATR (PubMed:16530042, PubMed:21777809). Also required for chromosomal stability when DSBs occur during mitosis by forming filamentous assemblies that bridge MDC1 and tether broken chromosomes during mitosis (PubMed:30898438). Together with CIP2A, plays an essential role in the response to genome instability generated by the presence of acentric chromosome fragments derived from shattered chromosomes within micronuclei (PubMed:35121901, PubMed:35842428, PubMed:37165191, PubMed:37316668). Micronuclei, which are frequently found in cancer cells, consist of chromatin surrounded by their own nuclear membrane: following breakdown of the micronuclear envelope, a process associated with chromothripsis, the CIP2A-TOPBP1 complex tethers chromosome fragments during mitosis to ensure clustered segregation of the fragments to a single daughter cell nucleus, facilitating re-ligation with limited chromosome scattering and loss (PubMed:37165191, PubMed:37316668). Recruits the SWI/SNF chromatin remodeling complex to E2F1-responsive promoters, thereby down-regulating E2F1 activity and inhibiting E2F1-dependent apoptosis during G1/S transition and after DNA damage (PubMed:12697828, PubMed:15075294).SUBUNIT Interacts (via BRCT domains 1 and 2) with (phosphorylated) MDC1; promoting TOPBP1 recruitment to DNA damage sites during mitosis (PubMed:21482717, PubMed:23891287, PubMed:30898438). Interacts (via BRCT domains 7 and 8) with (autophosphorylated) ATR; promoting activation of ATR (PubMed:21777809). Interacts (via BRCT domains 7 and 8) with (phosphorylated) POLQ; specifically binds POLQ phosphorylated by PLK1, promoting POLQ recruitment to DNA damage sites (PubMed:37674080). Interacts (via BRCT domains 1 and 2) with (phosphorylated) RAD9A (PubMed:11395493, PubMed:17575048, PubMed:20545769). Interacts (via BRCT domain 2) with (phosphorylated) TP53BP1 (PubMed:31135337). Interacts (via BRCT domain 2) with (phosphorylated) HTATSF1 (PubMed:35597237). Interacts (via BRCT domains 7 and 8) with (phosphorylated) RAD51; promoting RAD51 recruitment to damaged chromatin (PubMed:26811421). Interacts with CIP2A; forming the CIP2A-TOPBP1 complex (PubMed:35121901, PubMed:35842428, PubMed:37165191, PubMed:37316668). Interacts with POLE (PubMed:11395493). Interacts with UBR5 (PubMed:11714696). Interacts with E2F1 (PubMed:12697828, PubMed:15075294). Interacts with PML (PubMed:12773567). Interacts with SMARCA2 (PubMed:15075294). Interacts with SMARCA4 (PubMed:15075294). Interacts with RHNO1 (PubMed:21659603, PubMed:25602520). May interact with TOP2B (PubMed:9461304). Interacts with TICRR (PubMed:20080954). Interacts with HELB (PubMed:25933514). Interacts (via residues 1233-1522) with RECQL4 (PubMed:22730300).INTERACTION Localizes to sites of DNA damage, such as double-stranded breaks (DSBs) (PubMed:10498869, PubMed:21482717, PubMed:21659603, PubMed:21777809, PubMed:30898438, PubMed:35842428, PubMed:37674080). Recruited to DNA double-strand break (DSBs) during S-phase following interaction with phosphorylated HTATSF1 (PubMed:35597237). Recruited to DSBs during mitosis following interaction with phosphorylated MDC1 (PubMed:30898438). Has a uniform nuclear distribution during G phase (PubMed:11395493). Colocalizes with BRCA1 at stalled replication forks during S phase (PubMed:11395493). In mitotic cells it colocalizes with BRCA1 at spindle poles and centrosomes during metaphase and anaphase (PubMed:11395493). Detected in discrete foci together with PML and numerous DNA repair enzymes after DNA damage by alkylating agents, UV or gamma irradiation (PubMed:12773567). Detected on unpaired autosomes in meiotic prophase cells (By similarity). Detected on X and Y chromosomes during later stages of prophase (By similarity). Colocalizes with ATR and H2AX at unsynapsed chromosome cores during prophase (By similarity). Localizes to broken chromosomes within micronuclei during interphase and following chromothripsis (PubMed:37165191, PubMed:37316668). Localization to broken chromosomes is mainly independent of MDC1 (PubMed:35121901, PubMed:37165191).TISSUE SPECIFICITY Highly expressed in heart, brain, placenta, lung and kidney.INDUCTION Up-regulated during the S phase of the cell cycle. Up-regulated by E2F1 and interferon.DOMAIN Some BRCT domains specifically recognize and bind phosphoserine/phosphothreonine marks on proteins (PubMed:17575048, PubMed:20545769, PubMed:21777809, PubMed:23891287, PubMed:30898438, PubMed:31135337, PubMed:35597237, PubMed:37674080). BRCT domains 1 and 2 bind phosphorylated MDC1 and RAD9A (PubMed:17575048, PubMed:20545769, PubMed:30898438). BRCT domain 2 binds phosphorylated HTATSF1 and TP53BP1 (PubMed:31135337, PubMed:35597237). BRCT domains 7 and 8 bind phosphorylated ATR, POLQ and RAD51 (PubMed:21777809, PubMed:26811421, PubMed:37674080).PTM Phosphorylated on serine and threonine residues in response to X-ray irradiation.PTM Ubiquitinated and degraded by the proteasome. X-ray irradiation reduces ubiquitination (PubMed:11714696). Deubiquitinated by USP13; leading to TOPBP1 stabilizion and activation of the ATR-TOPBP1 axis pathway (PubMed:33592542).SIMILARITY Belongs to the TOPBP1 family.CAUTION Interaction with phosphorylated MDC1 was initially thought to be mediated by BRCT domains 4 and 5 (PubMed:23891287). However, it was later shown to be mainly mediated by BRCT domains 1 and 2 (PubMed:30898438).SEQUENCE CAUTION Extended N-terminus.SEQUENCE CAUTION Truncated N-terminus.
|
