Naked replication forks break apRPArt

Abstract

Stalled replication forks occasionally collapse, leading to potentially catastrophic DNA double-strand breaks. Now, Toledo et al. (2013) reveal that fork breakage occurs when the pool of the single-strand DNA-binding protein RPA becomes exhausted. This study has important implications for the origin and treatment of cancers with high levels of replicative stress.

Figure 1.. DNA Breaks Arising at Stalled Replication Forks

The figure classifies the different kinds of chromosome breaks that are induced by replication stress, on the basis of: the cell-cycle stage in which they occur (WHEN); the cause of the replication stress (WHY); the enzymes that produce the cleavage (HOW); and the signal that triggers the process (SIGNAL). The work of Toledo et al. demonstrates global breakage at every active fork when ssDNA is exposed through the exhaustion of the RPA pool. A more restricted activation of this process could initiate complex genomic rearrangements such as chromothripsis. To what extent the pathway revealed here contributes to DNA breaks that arise at specific fragile loci such as common fragile sites (CFS) or early replicating fragile sites (ERFS) remains to be determined.