The SIOD disorder protein SMARCAL1 is an RPA-interacting protein involved in replication fork restart.
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.
Howard Hughes Medical Institute and Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Alberto
A
Ciccia
Andrea L
AL
Bredemeyer
Mathew E
ME
Sowa
Marie-Emilie
ME
Terret
Prasad V
PV
Jallepalli
J Wade
JW
Harper
Stephen J
SJ
Elledge
D000595:Amino Acid Sequence; D002453:Cell Cycle; D002460:Cell Line; D004249:DNA Damage; D004265:DNA Helicases / Q000737:chemistry / Q000378:metabolism*; D004261:DNA Replication; D006801:Humans; D008969:Molecular Sequence Data; D010009:Osteochondrodysplasias / Q000235:genetics / Q000503:physiopathology*; D051716:Replication Protein A / Q000378:metabolism*; D016415:Sequence Alignment
D051716:Replication Protein A; C412482:SMARCAL1 protein, human; D004265:DNA Helicases