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

Research output: Contribution to journalArticlepeer-review

159 Scopus citations

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.

Original languageEnglish
Pages (from-to)2415-2425
Number of pages11
JournalGenes and Development
Volume23
Issue number20
DOIs
StatePublished - Oct 15 2009

Keywords

  • DNA double-strand breaks
  • DNA replication
  • DNA replication stress
  • HARP

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