FANCJ protein is important for the stability of FANCD2/FANCI proteins and protects them from proteasome and caspase-3 dependent degradation.
FANCJ protein is important for the stability of FANCD2/FANCI proteins and protects them from proteasome and caspase-3 dependent degradation.
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DOI：
10.18632/oncotarget.5006
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发表时间：
2015-10-06
期刊：
影响因子：
--
通讯作者：
Palle K
中科院分区：
文献类型：
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作者：
Clark DW;Tripathi K;Dorsman JC;Palle K
范可尼贫血（FA）是一种罕见的基因组不稳定综合征，伴有进行性骨髓衰竭和癌症易感性。FANCJ是FA患者中突变的17个基因之一，包含DNA解旋酶，其对于正确维持基因组稳定性至关重要，并且已知在FA-BRCA DNA修复途径中起作用。虽然FANCJ在该修复过程中的确切作用尚未确定，但已知其与主要效应物FANCD 2相互作用。然而，FANCJ不是FANCD 2激活所必需的，但对于其完全响应DNA损伤的能力很重要。在这份报告中，我们确定FANCJ的瞬时消耗对FANCD 2及其共调节因子FANCI在多种细胞系中的稳定性产生不利影响。FANCJ的缺失不会显著改变细胞周期进程或FANCD 2转录。然而，在不存在FANCJ的情况下，大多数FANCD 2通过蛋白酶体和胱天蛋白酶-3依赖性机制降解。FANCJ能够与FANCD 2复合并稳定FANCD 2，即使在不存在功能性解旋酶结构域的情况下。此外，我们的数据表明，FANCJ是重要的FANCD 2的稳定性和适当的激活DNA损伤反应的复制块诱导的羟基脲。
Fanconi anemia (FA) is a rare genome instability syndrome with progressive bone marrow failure and cancer susceptibility. FANCJ is one of 17 genes mutated in FA-patients, comprises a DNA helicase that is vital for properly maintaining genomic stability and is known to function in the FA-BRCA DNA repair pathway. While exact role(s) of FANCJ in this repair process is yet to be determined, it is known to interact with primary effector FANCD2. However, FANCJ is not required for FANCD2 activation but is important for its ability to fully respond to DNA damage. In this report, we determined that transient depletion of FANCJ adversely affects stability of FANCD2 and its co-regulator FANCI in multiple cell lines. Loss of FANCJ does not significantly alter cell cycle progression or FANCD2 transcription. However, in the absence of FANCJ, the majority of FANCD2 is degraded by both the proteasome and Caspase-3 dependent mechanism. FANCJ is capable of complexing with and stabilizing FANCD2 even in the absence of a functional helicase domain. Furthermore, our data demonstrate that FANCJ is important for FANCD2 stability and proper activation of DNA damage responses to replication blocks induced by hydroxyurea.