TOPBP1
Description
The TOPBP1 (DNA topoisomerase II binding protein 1) is a protein-coding gene located on chromosome 3.
DNA topoisomerase 2-binding protein 1 (TOPBP1) is a scaffold protein that in humans is encoded by the TOPBP1 gene. TOPBP1 was first identified as a protein binding partner of DNA topoisomerase-IIβ by a yeast 2-hybrid screen, giving it its name. TOPBP1 is involved in a variety of nuclear specific events. These include DNA damage repair, DNA replication, transcriptional regulation, and cell cycle checkpoint activation. TOPBP1 primarily regulates the DNA damage repair response through its ability to activate the damage response kinase, ataxia-telangiectasia mutated and RAD3-related (ATR). It also plays a critical role in DNA replication initiation and regulation of the cell cycle. Changes in TOPBP1 gene expression are associated with pulmonary hypertension, breast cancer, glioblastoma, non-small cell lung cancer, and sarcomas.
== Structure ==
=== BRCT domains === The TOPBP1 gene encodes a scaffold protein which facilitates interactions between different proteins at specific times and locations. It accomplishes these interactions with other protein partners through its breast cancer associated gene 1 C-terminus (BRCT) domains. A BRCT domain is structurally defined by a 4 member β sheet that is bookended by one α-helix (α2) and two other α-helices (α1 and α3).
TOPBP1 is a scaffold protein that acts as a key protein-protein adapter in DNA replication and DNA repair. It consists of multiple BRCT domains, which recognize and bind phosphorylated proteins, bringing proteins together into functional combinations. TOPBP1 is required for DNA replication initiation, but not for the formation of pre-replicative complexes or the elongation stages. It is necessary for the loading of replication factors onto chromatin, including GMNC, CDC45, DNA polymerases, and components of the GINS complex. TOPBP1 plays a central role in DNA repair by bridging proteins and promoting recruitment of proteins to DNA damage sites. It is 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. 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. TOPBP1 is involved in microhomology-mediated end-joining (MMEJ) DNA repair by promoting recruitment of polymerase theta (POLQ) to DNA damage sites during mitosis. 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. TOPBP1 recognizes and binds POLQ phosphorylated by PLK1, enabling its recruitment to DSBs for subsequent repair. It is involved in G1 DNA damage checkpoint by acting as a molecular adapter that couples TP53BP1 and the 9-1-1 complex. In response to DNA damage, TOPBP1 triggers the recruitment of checkpoint signaling proteins on chromatin, which activate the CHEK1 signaling pathway and block S-phase progression. It acts as an activator of the kinase activity of ATR. TOPBP1 is also required for chromosomal stability when DSBs occur during mitosis by forming filamentous assemblies that bridge MDC1 and tether broken chromosomes during mitosis. Together with CIP2A, TOPBP1 plays an essential role in the response to genome instability generated by the presence of acentric chromosome fragments derived from shattered chromosomes within micronuclei. 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. TOPBP1 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.
TOPBP1 is also known as Dpb11, TOP2BP1.
