Yuan Jingsong, Ghosal Gargi, Chen Junjie
Department of Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Genes Dev. 2009 Oct 15;23(20):2394-9. doi: 10.1101/gad.1836409. Epub 2009 Sep 30.
Mutations in HepA-related protein (HARP) are the only identified causes of Schimke immunoosseous dysplasia (SIOD). HARP has a unique annealing helicase activity in vitro, but the in vivo functional significance remains unknown. Here, we demonstrated that HARP is recruited to stalled replication forks via its direct interaction with Replication protein A (RPA). Cells with HARP depletion displayed increased spontaneous DNA damage and G2/M arrest, suggesting that HARP normally acts to stabilize stalled replication forks. Our data place the annealing helicase activity of HARP at replication forks and propose that SIOD syndrome may be caused by the destabilization of replication forks during cell proliferation.
甲型肝炎相关蛋白（HARP）的突变是已确定的导致施姆克免疫骨发育不良（SIOD）的唯一原因。HARP在体外具有独特的退火解旋酶活性，但其在体内的功能意义尚不清楚。在这里，我们证明HARP通过与复制蛋白A（RPA）的直接相互作用被招募到停滞的复制叉处。HARP缺失的细胞表现出自发性DNA损伤增加和G2/M期阻滞，这表明HARP通常起到稳定停滞复制叉的作用。我们的数据表明HARP的退火解旋酶活性存在于复制叉处，并提出SIOD综合征可能是由细胞增殖过程中复制叉的不稳定引起的。
