The Fanconi anemia proteins FANCA and FANCG stabilize each other and promote the nuclear accumulation of the Fanconi anemia complex
The Fanconi anemia proteins FANCA and FANCG stabilize each other and promote the nuclear accumulation of the Fanconi anemia complex
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DOI：
10.1182/blood.v96.9.3224.h8003224_3224_3230
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发表时间：
2000-11-01
期刊：
影响因子：
20.3
通讯作者：
D'Andrea, AD
中科院分区：
文献类型：
--
作者：
Garcia-Higuera, I;Kuang, Y;D'Andrea, AD
范可尼贫血 (FA) 是一种常染色体隐性遗传癌症易感性综合征，有 8 个互补组。四个 FA 基因已被克隆，并且至少 3 个编码的蛋白质（FANCA、FANCC 和 FANCG/XRCC9）在多亚基蛋白质复合物中相互作用。 FANCG蛋白直接结合FANCA的氨基末端核定位序列(NLS)，表明FANCG在调节FANCA核积累中发挥作用。在当前的研究中，检查了 FANCG/FANCA 结合的功能后果。用 FANCG 互补 DNA (cDNA) 校正 FA-G 细胞系导致 FANCA/FANCG 结合、FANCA 细胞半衰期延长以及 FA 蛋白复合物核积累增加。校正 FAA 细胞系后获得了类似的结果，FANCG 的半衰期相应增加，患者衍生的 FANCA 突变体形式包含完整的 NLS 序列，但羧基末端亮氨酸拉链区域有点突变，与细胞质中的 FANCG 结合。突变体形式未能易位至转导细胞的细胞核，从而提出了协调结合和核易位的模型。这些结果证明 FANCA/FANCG 相互作用是维持两种蛋白质的细胞水平所必需的。此外，FANCG和FANCA的至少一项功能是调节FA蛋白复合物的核积累。核 FA 蛋白复合物积累失败会导致 FA 中观察到的临床和细胞异常特征谱。 (C) 2000 年，美国血液学会。
Fanconi anemia (FA) is an autosomal recessive cancer susceptibility syndrome with 8 complementation groups. Four of the FA genes have been cloned, and at least 3 of the encoded proteins, FANCA, FANCC, and FANCG/XRCC9, interact in a multisubunit protein complex. The FANCG protein binds directly to the amino terminal nuclear localization sequence (NLS) of FANCA, suggesting that FANCG plays a role in regulating FANCA nuclear accumulation. In the current study the functional consequences of FANCG/FANCA binding were examined. Correction of an FA-G cell line with the FANCG complementary DNA (cDNA) resulted in FANCA/FANCG binding, prolongation of the cellular half-life of FANCA, and an increase in the nuclear accumulation of the FA protein complex. Similar results were obtained upon correction of an FAA cell line, with a reciprocal increase in the half-life of FANCG, Patient-derived mutant forms of FANCA, containing an intact NLS sequence but point mutations in the carboxy-terminal leucine zipper region, bound FANCG in the cytoplasm, The mutant forms failed to translocate to the nucleus of transduced cells, thereby suggesting a model of coordinated binding and nuclear translocation. These results demonstrate that the FANCA/FANCG interaction is required to maintain the cellular levels of both proteins. Moreover, at least one function of FANCG and FANCA is to regulate the nuclear accumulation of the FA protein complex. Failure to accumulate the nuclear FA protein complex results in the characteristic spectrum of clinical and cellular abnormalities observed in FA. (C) 2000 by The American Society of Hematology.