SMARCAL1 and replication stress: an explanation for SIOD?

Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
Nucleus (Austin, Texas) (Impact Factor: 3.15). 05/2010; 1(3):245-8. DOI: 10.4161/nucl.1.3.11739
Source: PubMed

ABSTRACT The SNF2 family of ATPases acts in the context of chromatin to regulate transcription, replication, repair and recombination. Defects in SNF2 genes cause many human diseases. For example, mutations in SMARCAL1 (also named HARP) cause Schimke immuno-osseous dysplasia (SIOD); a multi-system disorder characterized by growth defects, immune deficiencies, renal failure and other complex phenotypes. Several groups including ours recently identified SMARCAL1 as a replication stress response protein. Importantly, SMARCAL1 localizes to stalled replication forks and this localization of SMARCAL1 activity prevents DNA damage accumulation during DNA replication. We determined that SIOD-related SMARCAL1 mutants could not prevent replication-associated DNA damage in cells in which endogenous SMARCAL1 was silenced, establishing the first link between SIOD and a defect in a specific biological activity. Here, we also report that cells from patients with SIOD exhibit elevated levels of DNA damage that can be rescued by re-introduction of wild-type SMARCAL1. Our data suggest that loss of SMARCAL1 function in patients may cause DNA replication-associated genome instability that contributes to the pleiotropic phenotypes of SIOD.

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    ABSTRACT: SMARCAL1 is a SNF2 chromatin-remodeling protein with ATP-dependent annealing helicase activity. Recent studies have shown that SMARCAL1 is involved in DNA damage repair and cell cycle progression. Deficiency of SMARCAL1 enhances the anticancer activity of chemotherapy agents and reverses cancer cell resistance to these agents. Therefore, targeting SMARCAL1 is an attractive therapeutic approach for cancers with defects in DNA damage repair or cell cycle checkpoints. Here, we review advances in our understanding of the biochemical and cellular functions of SMARCAL1 made over the recent years and discuss the rationale for development of SMARCAL1 inhibitors as novel anticancer therapies.
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