• Maintaining genomic integrity is of utmost importance to eukaryotic cells, which have evolved sophisticated mechanisms to ensure speed, accuracy, and an adequate pool of nucleotide and replication factors as well as high-fidelity repair pathways to correct errors occurring during DNA replication. (bmj.com)
  • It is hypothesized that one pathway may be most active when ATR is carrying out normal support for replicating cells, and the other may be active when the cell is under more extreme replicative stress. (wikipedia.org)
  • Strategies that increase replicative stress while lowering cell cycle checkpoint thresholds may allow unrepaired DNA damage to be inappropriately carried forward in replicating cells, leading to mitotic catastrophe and cell death. (bmj.com)
  • Any obstacles encountered by cells in this process can lead to 'replicative stress' ( Figure 1 ), 1 which may be overcome by replicative stress response proteins, but deficiencies in this response result in accumulated errors in DNA replication and loss of genomic integrity, which lead to cell death. (bmj.com)
  • through the Chk1-CDC25 pathway, which effects levels of CDC2, this response is thought to reduce the rate of DNA synthesis in the cell and inhibit origin firing during replication. (wikipedia.org)
  • Each origin is initiated by a combination of regulatory proteins that prepare the chromatin for replication before synthesis (S)-phase entry. (bmj.com)
  • Then hTopBP1 interacts with ATR-ATRIP through its ATR-activating domain (AD) and stimulates ATR kinase activity [ 8 , 9 ]. (biomedcentral.com)
  • It is hypothesized that this pathway, which works independently of TOPBP1 pathway, is used to divide labor and possibly respond to differential needs within the cell. (wikipedia.org)
  • An experiment where RAD9, ATRIP, and TOPBP1 were overexpressed proved that these proteins alone were enough to activate ATR in the absence of ssDNA, showing their importance in triggering this pathway. (wikipedia.org)
  • Human DNA topoisomerase II-binding protein 1 (hTopBP1) plays an important role in DNA replication and the DNA damage checkpoint pathway. (biomedcentral.com)
  • Thus, hTopBP1 constitutes an important part of the ATR signaling pathway and acts as a molecular bridge that associates the independently recruited 9-1-1 and ATR-ATRIP complexes, thereby leading to checkpoint activation [ 4 ]. (biomedcentral.com)
  • This complex also brings in topoisomerase binding protein 1 (TOPBP1) which binds ATR through a highly conserved AAD. (wikipedia.org)
  • Human DNA topoisomerase II-binding protein 1 (TopBP1) and its orthologs play important roles in DNA replication and checkpoint control [ 1 ]. (biomedcentral.com)
  • The protein encoded by this gene belongs the PI3/PI4-kinase family, and is most closely related to ATM, a protein kinase encoded by the gene mutated in ataxia telangiectasia. (utsouthwestern.edu)
  • ATR belongs to the phosphatidylinositol 3-kinase-related kinase protein family. (wikipedia.org)
  • ATR is activated during every S phase, even in normally cycling cells, as it works to monitor replication forks to repair and stop cell cycling when needed. (wikipedia.org)
  • During ATR signaling in response to DNA damage, Rad17 forms a complex with 9-1-1 and loads onto stalled replication forks [ 4 - 9 ]. (biomedcentral.com)
  • Essential gene? (utsouthwestern.edu)
  • Our results suggested that hMYH is necessary for the accumulation of hTopBP1 to DNA damage lesion to induce the association of hTopBP1 with 9-1-1 and that the interaction between hMYH and hTopBP1 is essential for Chk1 activation. (biomedcentral.com)
  • Through its interactions with other proteins via its BRCT domains, hTopBP1 performs diverse functions [ 1 ]. (biomedcentral.com)
  • Small molecule inhibitors designed to target the DNA damage sensors, such as inhibitors of ataxia telangiectasia-mutated (ATM), ATR, CHK1 and WEE1, impair smooth cell cycle modulation and disrupt efficient DNA repair, or a combination of the above, have demonstrated interesting monotherapy and combinatorial activity, including the potential to reverse drug resistance and have entered developmental pipelines. (bmj.com)
  • In the presence of errors or damage during DNA replication, cell cycle checkpoint nodes and repair machinery work in concert to retard cell cycle progression until sufficient repair has been achieved. (bmj.com)
  • This claspin intermediate needs to be phosphorylated at two sites in order to do this job, something that can be carried out by ATR but is most likely under the control of some other kinase. (wikipedia.org)
  • Instead, ATR activation is heavily dependent on the existence of all the proteins previously described, that colocalize around the site of DNA damage. (wikipedia.org)
  • Many other proteins exist that are recruited to the cite of ssDNA that are needed for ATR activation. (wikipedia.org)
  • This means that ATR is activated at normal, background levels within all healthy cells. (wikipedia.org)
  • Therefore, we suggest that the interaction between hMYH and hTopBP1 is crucial for activation of the ATR-mediated cell cycle checkpoint. (biomedcentral.com)
  • For effective association of the 9-1-1 complex with DNA, RAD17-RFC is also needed. (wikipedia.org)
  • Another important protein that binds TR was identified by Haahr et al. (wikipedia.org)