Human SLX4 is a Holliday junction resolvase subunit that binds multiple DNA repair/recombination endonucleases.
Human SLX4 is a Holliday junction resolvase subunit that binds multiple DNA repair/recombination endonucleases.
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DOI：
10.1016/j.cell.2009.06.029
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发表时间：
2009-07-10
期刊：
影响因子：
64.5
通讯作者：
Gaillard PHL
中科院分区：
文献类型：
--
作者：
Fekairi S;Scaglione S;Chahwan C;Taylor ER;Tissier A;Coulon S;Dong MQ;Ruse C;Yates JR 3rd;Russell P;Fuchs RP;McGowan CH;Gaillard PHL
结构特异性核酸内切酶解析DNA修复和重组过程中产生的DNA二级结构。酵母5′-瓣状核酸内切酶Slx 1-Slx 4受到了特别的关注，发现Slx 4在基因组维持中具有不依赖于Slx 1的关键功能。虽然Slx 1在真核生物中是一个高度保守的蛋白质，但除了真菌外，没有报道Slx 4的直系同源物。在这里，我们报告的鉴定Slx 4的直系同源的后生动物，包括苍蝇MUS 312，减数分裂重组所必需的，和人类BTBD 12，ATM/ATR检查点激酶底物。人SLX 1-SLX 4除了5′-瓣状核酸内切酶活性外，还显示出稳健的霍利迪连接解离酶活性。SLX 1和SLX 4的消耗导致53 BP 1病灶积累和H2 AX磷酸化以及对MMS的细胞超敏性。此外，我们表明SLX 4结合XPF和MUS 81亚基的XPF-ERCC 1和MUS 81-EME 1内切核酸酶，是DNA链间交联修复所需的。我们建议SLX 4作为多个结构特异性核酸内切酶的对接平台。
Structure-specific endonucleases resolve DNA secondary structures generated during DNA repair and recombination. The yeast 5′-flap endonuclease Slx1-Slx4 has received particular attention with the finding that Slx4 has Slx1-independent key functions in genome maintenance. Although Slx1 is a highly conserved protein in eukaryotes, no orthologs of Slx4 were reported other than in fungi. Here we report the identification of Slx4 orthologs in metazoa, including fly MUS312, essential for meiotic recombination, and human BTBD12, an ATM/ATR checkpoint kinase substrate. Human SLX1-SLX4 displays robust Holliday junction resolvase activity in addition to 5′-flap endonuclease activity. Depletion of SLX1 and SLX4 results in 53BP1 foci accumulation and H2AX phosphorylation as well as cellular hypersensitivity to MMS. Furthermore, we show that SLX4 binds the XPF and MUS81 subunits of the XPF-ERCC1 and MUS81-EME1 endonucleases and is required for DNA interstrand crosslink repair. We propose that SLX4 acts as a docking platform for multiple structure-specific endonucleases.
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