A novel mechanism granting structural protection of replication forks, the structures in which DNA is synthesised, has been uncovered by the DNA replication and Genome Integrity group led by Dr. Rodrigo Bermejo at CIB.
DNA holds genetic information and is organized in higher order structures named chromosomes. In order for cells to divide, chromosomal DNA needs to be duplicated while its structural integrity is maintained. However, problems during replication can lead to breaks and alterations that underlie the initial stages of cancer development.
This study reveals the existence of a mechanism that coordinates the function of the structural maintenance of chromosomes cohesin complex with the progression of replication forks. Cohesin forms a molecular ring that binds chromosomes and entraps DNA molecules after they are duplicated to ensure that they are properly passed on to daughter cells.
By the combination of state-of-the-art genetics, genomics and molecular biology approaches the team found that, when engaged by replication forks, cohesin rings are ubiquitylated (by the Rsp5Bul2 ligase) and this triggers their mobilization (by the Cdc48 segregase and the cohesin-associated factor Wapl1) to entrap the daughter DNA molecules and structurally stabilize newly forming chromosomes. If this mechanism fails, replication forks cannot properly duplicate DNA and prime changes in the genetic information.
Furthermore, Bermejo’s group discovery helps to provide insight on why may cohesin mutations be associated to the development of a large number of human cancers.
Reference: Cohesin ubiquitylation and mobilization facilitate stalled replication fork dynamics. Camilla Frattini, Sara Villa-Hernández, Grazia Pellicanò, Rachel Jossen, Yuki Katou, Katsuhiko Shirahige, Rodrigo Bermejo. Molecular Cell (2017) DOI: http://dx.doi.org/10.1016/j.molcel.2017.10.012
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