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发布于:2020-11-27 13:53:29  访问:1 次 回复:0 篇
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The DNA endtethering activity of MRN may also facilitate ATM activation by increasing the local concentration of DNA ends. In vitro, MRN directly stimulates the binding of ATM to its substrates even in the absence of DNA. The key event driving this process is the phosphorylation of the histone variant HAX by ATM.Mdc also interacts with ATM through its FHA domain. In addition to HAX phosphorylation, the kinase activity of ATM contributes to its chromatin binding in several other ways.The ATM recruited to chromatin may be regulated by additional mechanisms.In contrast to NHEJ, HR is an errorfree repair pathway.HR not only requires homologous DNA sequences as repair templates, but also ssDNA ends to search for homologous sequences.Using an in vitro assay that monitors the activation of both ATM and ATR by dsDNA, resection of DNA ends was found to induce ATR activation, but progressively attenuates the ability of dsDNA to activate ATM. This essentiality is likely caused by the fact that ATR monitors replication fork progression and is required to protect cells from intrinsic replication stress that occurs during unperturbed S phase. Studies in yeast and metazoans have shown that ATR maintains genome stability by phosphorylating a large number of substrates including proteins that function at replication forks and origins.These phosphorylation events may protect the genome during DNA synthesis by regulating nucleotide levels, fork progression, origin ring, and cellcycle transitions, and activating specic DNA repair pathways to promote complete and accurate replication of the genome. A failsafe, multistep mechanism for ATR activation.Increased amounts of ssDNA are generated by resection of DNA ends or by uncoordinated DNA unwinding and synthesis at replication forks.Extensively resected DNA ends are no longer recognized by ATM efciently.Once coated by RPA, ssDNA recruits the ATRATRIP complex. TopBP may also function as a scaffold to facilitate ATR substrate recognition.In vivo and in vitro studies suggest that at least three regulatory Targetmol‘s Delafloxacin mechanisms contribute to the full activation of the ATR pathway.Second, the kinase activity of ATR is stimulated by specic regulators on damaged DNA.Third, through a series of phosphorylationmediated protein protein interactions, ATR forms a dynamic signaling complex with its substrates.All these mechanisms are regulated by damaged DNA and are intertwined with each other.Only when these mechanisms operate in concert is ATR able to signal DNA damage or DNA replication stress at its full capacity.In budding yeast, the yeast ortholog of the clamp. It is still unclear whether the clamp directly activates ATR in vertebrates.These mechanisms may act together to ensure that ATR is only activated in which both ssDNA and ssDNA dsDNA junctions are present, but not by ssDNA alone, making ATR activation a unique failsafe event that responds only in the presence of a specic spectrum of DNA damage.The full activation of ATR signaling requires not only ATR itself and DNA damage sensors, but also proteins that function as signal transducers and effectors.Importantly, many of these proteins have been shown to interact with each other in an ATR and phosphorylationmediated manner, suggesting a critical role for ATR in the assembly of a signaling complex.
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