SMARCAL1 and telomeres: Replicating the troublesome ends.

DNA replication is constantly challenged by both endogenous and exogenous sources of replication stress. SMARCAL1, an SNF2 family DNA translocase, functions in the DNA damage response to address these obstacles and promote the completion of replication. Most studies examining the function of SMARCAL1 and related enzymes have relied on the addition of exogenous genotoxic agents, but SMARCAL1 is needed even in the absence of these drugs to maintain genome stability during DNA replication. We recently determined that SMARCAL1 functions to limit DNA damage during replication of difficult-to-replicate telomere sequences. SMARCAL1-deficient cells display several markers of telomere instability including extrachromosomal telomere circles and co-localization with DNA damage markers. Furthermore, cells lacking the highly related proteins ZRANB3 and HLTF do not exhibit similar problems suggesting a unique function for SMARCAL1. These studies identified the first source of endogenous replication stress that SMARCAL1 resolves and provide insight into the mechanism of SMARCAL1 function in maintaining genome stability.