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

Alberto Ciccia; Andrea L. Bredemeyer; Mathew E. Sowa; Marie-Emilie Terret; Prasad V. Jallepalli; J. Wade Harper; Stephen J. Elledge

doi:10.1101/gad.1832309

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

¹Howard Hughes Medical Institute and Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA;
²Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA;
³Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA

↵4 These authors contributed equally to this work.

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.

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Footnotes

↵5 Corresponding author.

E-MAIL selledge{at}genetics.med.harvard.edu; FAX (617) 525-4500.
Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1832309.
Supplemental material is available at http://www.genesdev.org.
- Received June 15, 2009.
- Accepted August 31, 2009.