'Guardian of the Genome': Protein Helps Prevent Damaged DNA in Yeast
ScienceDaily (Aug. 1, 2010) — Like a scout that runs ahead to spot signs of damage or danger, a protein in yeast safeguards the yeast cells' genome during replication -- a process vulnerable to errors when DNA is copied -- according to new Cornell research.
Researchers from Cornell University's Weill Institute for Cell and Molecular Biology have discovered how a protein called Mec1 plays the role of "guardian of the genome," explained Marcus Smolka, assistant professor of molecular biology and genetics. The findings are detailed in the journal Molecular Cell.
Previous studies have shown that cells lacking Mec1 accumulate damaged DNA and become more sensitive to agents that interfere with replication. The researchers report that the Mec1 protein monitors and repairs the machinery responsible for replicating the DNA. At times, when DNA becomes damaged, the replication machinery can actually detach from the DNA -- like a train coming off a track -- but Mec1 coordinates the repair of the machinery and the DNA itself, allowing it to restart and continue replicating.
"Mec1 organizes the cell's response against things that jeopardize the integrity of the genome," Smolka said.
During the replication process, Mec1 accumulates at trouble spots such as lesions in the DNA or other blocks to replication. Mec1 is known as a kinase, a type of enzyme that modifies other proteins by adding a phosphate group to them (a process called phosphorylation), which then leads to a functional change in the protein. The researchers report that Mec1 adds a phosphate group to a protein known as Slx4, which then triggers Slx4 to anchor to the replication machinery. Slx4 then can employ a variety of tools to repair DNA and the replication machinery.
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Read more here/Leia mais aqui: Science Daily
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doi:10.1016/j.molcel.2010.06.019
DNA Damage Signaling Recruits the Rtt107-Slx4 Scaffolds via Dpb11 to Mediate Replication Stress Response
Patrice Y. Ohouo1, 2, 3, Francisco M. Bastos de Oliveira2, 3, Beatriz S. Almeida2 and Marcus B. Smolka2, ,
1 Graduate Program in Biochemistry, Molecular and Cell Biology, Weill Institute for Cell and Molecular Biology, Cornell University, 339 Weill Hall, Ithaca, New York 14853-7202, USA
2 Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, 339 Weill Hall, Ithaca, New York 14853-7202, USA
Corresponding author
3 These authors contributed equally to this work
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Highlights
Summary
- The DNA damage checkpoint kinase Mec1ATR is critical for maintaining the integrity of replication forks. Though it has been proposed to promote fork repair, the mechanisms by which Mec1 regulates DNA repair factors remain unclear. Here, we found that Mec1 mediates a key interaction between the fork protein Dpb11 and the DNA repair scaffolds Slx4-Rtt107 to regulate replication stress response. Dissection of the molecular basis of the interaction reveals that Slx4 and Rtt107 jointly bind Dpb11 and that Slx4 phosphorylation is required. Mutation of Mec1 phosphorylation sites in Slx4 disrupts its interaction with Dpb11 and compromises the cellular response to replisomes blocked by DNA alkylation. Multiple fork repair factors associate with Rtt107 or Slx4, supporting that Mec1-dependent assembly of the Rtt107-Slx4-Dpb11 complex functions to coordinate fork repair. Our results unveil how Mec1 regulates the Slx4 and Rtt107 scaffolds and establish a mechanistic link between DNA damage signaling and fork repair.
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► Mec1 mediates interaction between Dpb11 and the Rtt107-Slx4 scaffolds ► Mutation of canonical Mec1 phosphosites in Slx4 disrupts its interaction with Dpb11 ► Disruption of Dpb11-Slx4 interaction results in sensitivity to replication stress
Palavras salientadas em vermelho para destacar a linguagem teleológica do abstract. Os autores da pesquisa não são proponentes do Design Inteligente: são as evidências encontradas na natureza que revelam teleologia, e os cientistas não puderam dizer o contrário.
Design inteligente ou mero acaso, fortuita necessidade via seleção natural y otros mecanismos evolutivos ao longo das eras???
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Os brasileiros são Francisco M. Bastos de Oliveira, Beatriz S. Almeida e Marcus B. Smolka. O Dr. Marcus B. Smolka dirige o Laboratory of Proteomics and Cell Signaling na Cornell University. Smolka recebeu apoio financeiro da FAPESP na sua formação acadêmica e fez parte da equipe do Prof. Dr. José Camillo Novello, da Unicamp, que trabalhou com o produto dos genes, as proteínas.
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