SMARCAL1 and replication stress: an explanation for SIOD?

Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
Nucleus (Austin, Texas) (Impact Factor: 3.03). 05/2010; 1(3):245-8. DOI: 10.4161/nucl.1.3.11739
Source: PubMed


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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Available from: Cornelius F Boerkoel, Aug 14, 2015
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    • "The finding of parental consanguinity in these cases is highly suggestive of an underlying recessive cause. For example, following the array study, case 012 was diagnosed with Schimke immune-osseous dysplasia, an autosomal-recessive pleiotropic disorder caused by loss of function mutations in SMARCAL1 leading to spondyloepiphyseal dysplasia, renal dysfunction and T-cell immunodeficiency [20,21]. A diagnosis of autosomal recessive spinal muscular atrophy has been suspected in case 009. "
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    • "SMARCAL1 mutants derived from SIOD patients fail to rescue the genome maintenance defects caused by SMARCAL1 deficiency (Bansbach et al. 2009, 2010; Yuan et al. 2009). Thus, SMARCAL1 acts at damaged replication forks to maintain genome stability, and defects in this activity may underlie at least some of the phenotypes associated with SIOD (Bansbach et al. 2010). "
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