Blame ATAD5 for factory closures

Lee et al. show how a protein linked to cancer helps cells shut down DNA replication sites.

DNA duplication begins at multiple nearby sites, so-called replication factories that teem with enzymes. Cells eventually close the factories, but researchers don’t know what determines their longevity. One key replication factory protein is proliferating cell nuclear antigen (PCNA), which clamps onto DNA and helps DNA polymerase move along the strand. Lee et al. previously demonstrated that ATAD5 removes ubiquitin from PCNA together with a deubiquitinating enzyme. However, mice defective in ATAD5 were cancer prone, whereas mice defective in the enzyme were not. Thus, Lee et al. investigated whether ATAD5 affects other aspects of PCNA function.

In cells lacking ATAD5, replication factories lingered on the DNA, often into G2, the researchers found. Many of these long-lived factories were inert during S phase. The absence of ATAD5 slowed DNA duplication and delayed the completion of S phase. Whereas most control cells had exited S phase within nine hours, more than 40% of cells missing ATAD5 had not moved on after that amount of time. In cells where ATAD5 was missing, Lee et al. determined, PCNA adhered to DNA, forming extra-large clusters. This suggests that ATAD5 controls the lifespan of replication factories by dislodging PCNA from DNA.

Just because a factory closes doesn’t mean PCNA is out of a job. Cells have a limited supply of PCNA, and bumping the protein from DNA might allow it to transfer to new replication locations. Mutations in ATAD5 spur cancer in mice and humans. The researchers think that the mutations trigger cancer by disrupting removal of the replication factories and holding many replication or repair enzymes there.