SMARCAL1: a DNA repair protein recruited to double-strand breaks at stalled replication forks to promote genome stability through a homologous recombination pathway
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
To create an exact copy of the entire genome, replication should be completed promptly and accurately. However, obstacles can arise during replication that can cause genotoxic fork stalling. The DNA damage response pathway plays a crucial role in preventing fork collapse by stabilizing the stalled fork, regulating DNA repair, and promoting replication restart. There are multiple pathways to recover stalled replication forks, including double-strand break (DSB)-mediated recovery. SMARCAL1, a damage-binding protein involved in stabilizing stalled replication forks during DNA repair, is recruited to replication forks via interaction with replication protein A (RPA), the major ssDNA-binding protein in eukaryotic cells; however, the process by which it promotes DSB repair is poorly understood. Here, we present cellular and biochemical evidence that SMARCAL1 c.1920_1921insG frameshift mutation impairs SMARCAL1 protein expression causing defects in DNA damage response and hypersensitivity to several genotoxic agents that cause DSBs and replication fork collapse in a patient with Schimke immuno-osseous dysplasia. We analyzed the role of SMARCAL1 in the two major DNA DSB repair pathways, homologous recombination (HR) and nonhomologous end-joining (NHEJ). γ-H2AX foci repair kinetics analysis and survival experiments performed in SMARCAL1-deficient fibroblasts point to an essential role for SMARCAL1 in repairing DSBs generated in the S/G2 phase cell cycle as a result of oxidative damage and replication stress. The contribution to survival of SMARCAL1-dependent DSB rejoining in the S/G2 phase cell cycle suggests that SMARCAL1 is a novel damage repair protein involved in the HR pathway.