The SIOD disorder protein SMARCAL1 is an RPA-interacting protein involved in replication fork restart

Abstract

The integrity of genomic DNA is continuously challenged by the presence of DNA base lesions or DNA strand breaks. Here we report the identification of a new DNA damage response protein, SMARCAL1 (SWI/SNF-related, matrix associated, actin-dependent regulator of chromatin, subfamily a-like 1), which is a member of the SNF2 family and is mutated in Schimke immunoosseous dysplasia (SIOD). We demonstrate that SMARCAL1 directly interacts with Replication protein A (RPA) and is recruited to sites of DNA damage in an RPA-dependent manner. SMARCAL1-depleted cells display sensitivity to DNA-damaging agents that induce replication fork collapse, and exhibit slower fork recovery and delayed entry into mitosis following S-phase arrest. Furthermore, SIOD patient fibroblasts reconstituted with SMARCAL1 exhibit faster cell cycle progression after S-phase arrest. Thus, the symptoms of SIOD may be caused, at least in part, by defects in the cellular response to DNA replication stress.[Keywords: HARP; DNA replication; DNA double-strand breaks; DNA replication stress] Supplemental material is available at http://www.genesdev.org.

hPrimpol1/CCDC111 is a human DNA primase‐polymerase required for the maintenance of genome integrity

“…We propose that, in response to replication stress, replication forks would be stalled and allow the formation of ssDNA regions that become coated with RPA. Through the interaction with RPA1, hPrimpol1, SMARCAL1/HARP [5][6][7][8][9] and/or other RPAbinding proteins are recruited to these stalled replication forks and exerts their enzymatic activities to reinitiate DNA replication and thus to limit replication-associated DNA damage (Fig 5G). …”

Transcriptional and posttranscriptional mechanisms contribute to the dysregulation of elastogenesis in Schimke immuno-osseous dysplasia

“…SMARCAL1 could alter the local structure of DNA thereby promoting or inhibiting the transcription of specific genes via a direct effect of SMARCAL1 deficiency on the gene of interest (e.g., ELN) or from an indirect effect of SMARCAL1 deficiency on upstream pathways (e.g., increased expression of miR-29 family members, altered expression of the pathway regulating ELN poly(A) tail length, etc.). We hypothesize that SMARCAL1 deficiency mediates these effects by altering the epigenetic landscape as a consequence of its role in the DNA damage response (4,5) and replication fork restart (6)(7)(8). Replication fork stalling is associated with epigenetic instability (36); consequently, if SMARCAL1 replication fork stalling occurred near ELN or key regulators of ELN and ELN mRNA stability, the resulting epigenetic changes might produce the pathogenic gene expression alterations observed in the SIOD aorta.…”

“…SMARCAL1 functions as a DNA-dependent annealing helicase (2) that recognizes single-stranded to double-stranded DNA transitions and binds to transcriptionally active chromatin (3). SMARCAL1 is involved in the DNA stress response (4,5), the reactivation of stalled replication forks (6)(7)(8), and the modulation of gene expression (3). Key manifestations of the disease include growth failure due to spondyloepiphyseal dysplasia, renal failure due to focal segmental glomerulosclerosis, T-cell immunodeficiency, facial dysmorphism, and hyperpigmented macules (9).…”

Replication stress and cancer: It takes two to tango

“…Although PICH might not be directly involved in the dissolution of the bridge, it is required to stabilize the DNA and recruit BLM to allow their repair [61]. Second, the SMARCAL1 helicase is recruited to stalled forks, interacts with WRN and RPA, and is essential for the restart of forks after stress [62][63][64]. Defects in SMARCAL1 are the cause of the Schimke immunoosseous dysplasia (Siod) that is characterized by growth retardation, skeletal abnormalities and a severe immunodeficiency.…”