Involvement of p54(nrb), a PSF partner protein, in DNA double-strand break repair and radioresistance.
Involvement of p54(nrb), a PSF partner protein, in DNA double-strand break repair and radioresistance.
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DOI：
10.1093/nar/gkp741
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发表时间：
2009-11
影响因子：
14.9
通讯作者：
Dynan WS
中科院分区：
文献类型：
--
作者：
Li S;Kuhne WW;Kulharya A;Hudson FZ;Ha K;Cao Z;Dynan WS
哺乳动物细胞通过直接非同源DNA末端连接(NHEJ)和同源重组(HR)等有效途径修复DNA双链断裂。先前的工作已经确定PSF和p54(NRB)两个多肽的复合体是重组的体外NHEJ系统中的刺激因子。PSF还可在体外刺激HR的早期步骤。PSF和p54(NRB)是含有RNA识别基序的蛋白质，在RNA处理和运输中具有成熟的功能，它们明显参与DSB修复是意想不到的。在此，我们研究了体内DSB修复过程中对p54(NRB)的需求。在γ-H_2AX焦点实验中，用siRNA减弱p54(Nrb)表达的细胞显示出dsb修复的延迟。P54(NRB)miRNA转染获得的稳定基因敲除细胞系显示电离辐射诱发的染色体畸变率显著增加。在克隆存活试验中，它们也显示出更高的放射敏感性。总之，结果表明，p54(NRB)有助于在人体细胞中快速准确地修复DSB，因此PSF·p54(NRB)复合体可能成为辐射增敏剂开发的潜在靶点。
Mammalian cells repair DNA double-strand breaks (DSBs) via efficient pathways of direct, nonhomologous DNA end joining (NHEJ) and homologous recombination (HR). Prior work has identified a complex of two polypeptides, PSF and p54(nrb), as a stimulatory factor in a reconstituted in vitro NHEJ system. PSF also stimulates early steps of HR in vitro. PSF and p54(nrb) are RNA recognition motif-containing proteins with well-established functions in RNA processing and transport, and their apparent involvement in DSB repair was unexpected. Here we investigate the requirement for p54(nrb) in DSB repair in vivo. Cells treated with siRNA to attenuate p54(nrb) expression exhibited a delay in DSB repair in a γ-H2AX focus assay. Stable knockdown cell lines derived by p54(nrb) miRNA transfection showed a significant increase in ionizing radiation-induced chromosomal aberrations. They also showed increased radiosensitivity in a clonogenic survival assay. Together, results indicate that p54(nrb) contributes to rapid and accurate repair of DSBs in vivo in human cells and that the PSF·p54(nrb) complex may thus be a potential target for radiosensitizer development.
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