Mouse SLX4 Is a Tumor Suppressor that Stimulates the Activity of the Nuclease XPF-ERCC1 in DNA Crosslink Repair

HodskinsonM.R.G.; SilhanJ.; CrossanG.P.; GaraycoecheaJ.I.; MukherjeeS.; JohnsonC.M.; Sch?rerO.D.; PatelK.J.

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Mouse SLX4 Is a Tumor Suppressor that Stimulates the Activity of the Nuclease XPF-ERCC1 in DNA Crosslink Repair

机译：小鼠SLX4是一种肿瘤抑制因子，可刺激DNA交联修复中的核酸酶XPF-ERCC1的活性。

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SLX4 binds to three nucleases (XPF-ERCC1, MUS81-EME1, and SLX1), and its deficiency leads to genomic instability, sensitivity to DNA crosslinking agents, and Fanconi anemia. However, it is not understood how SLX4 and its associated nucleases act in DNA crosslink repair. Here, we uncover consequences of mouse Slx4 deficiency and reveal its function in DNA crosslink repair. Slx4-deficient mice develop epithelial cancers and have a contracted hematopoietic stem cell pool. The N-terminal domain of SLX4 (mini-SLX4) that only binds to XPF-ERCC1 is sufficient to confer resistance to DNA crosslinking agents. Recombinant mini-SLX4 enhances XPF-ERCC1 nuclease activity upto 100-fold, directing specificity toward DNA forks. Mini-SLX4-XPF-ERCC1 also vigorously stimulates dual incisions around a DNA crosslink embedded ina synthetic replication fork, an essential step in the repair of this lesion. These observations define vertebrate SLX4 as a tumor suppressor, which activates XPF-ERCC1 nuclease specificity in DNA crosslink repair.

机译：SLX4与三种核酸酶（XPF-ERCC1，MUS81-EME1和SLX1）结合，其缺乏会导致基因组不稳定，对DNA交联剂的敏感性和Fanconi贫血。但是，尚不了解SLX4及其相关的核酸酶在DNA交联修复中的作用。在这里，我们揭示了小鼠Slx4缺乏症的后果，并揭示了其在DNA交联修复中的功能。 Slx4缺陷小鼠发展上皮癌，并具有造血干细胞池收缩。仅与XPF-ERCC1结合的SLX4（微型SLX4）的N末端结构域足以赋予对DNA交联剂的抗性。重组mini-SLX4可将XPF-ERCC1核酸酶活性提高至100倍，从而将特异性指向DNA叉。 Mini-SLX4-XPF-ERCC1还可以强烈刺激合成复制叉中嵌入的DNA交联周围的双重切口，这是修复该病变的关键步骤。这些发现将脊椎动物SLX4定义为一种肿瘤抑制因子，可激活DNA交联修复中的XPF-ERCC1核酸酶特异性。

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《Molecular cell》 |2014年第3期|共13页
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HodskinsonM.R.G.; SilhanJ.; CrossanG.P.; GaraycoecheaJ.I.; MukherjeeS.; JohnsonC.M.; Sch?rerO.D.; PatelK.J.;
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正文语种 eng
中图分类细胞生物学;
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2. Mouse SLX4 Is a Tumor Suppressor that Stimulates the Activity of the Nuclease XPF-ERCC1 in DNA Crosslink Repair [J] . HodskinsonM.R.G., SilhanJ., CrossanG.P., Molecular cell . 2014,第3期

机译：小鼠SLX4是一种肿瘤抑制因子，可刺激DNA交联修复中的核酸酶XPF-ERCC1的活性。
3. The role of SLX4 and its associated nucleases in DNA interstrand crosslink repair [J] . Wouter S Hoogenboom, Rick A C M Boonen, Puck Knipscheer Nucleic acids research . 2019,第5期

机译：SLX4及其相关核酸酶在DNA链间交联修复中的作用
4. MEN1 Is a Melanoma Tumor Suppressor That Preserves Genomic Integrity by Stimulating Transcription of Genes That Promote Homologous Recombination-Directed DNA Repair [J] . Minggang Fang, Fen Xia, Meera Mahalingam, Molecular and Cellular Biology . 2013,第13期

机译：MEN1是一种黑色素瘤肿瘤抑制因子，可通过刺激促进同源重组指导的DNA修复的基因转录来保持基因组完整性。
5. In Situ Analysis of DNA Repair Processes of Tumor Suppressor BRCA1 [C] . Leizhen Wei, Natsuko Chiba International Conference on Biomedical Engineering . 2008

机译：肿瘤抑制剂BRCA1 DNA修复过程的原位分析
6. SAN1 - A Novel Nuclease Involved in DNA Interstrand Crosslink Repair [D] . McCartney, Heather Joan 2018

机译：SAN1-涉及DNA链间交联修复的新型核酸酶
7. Mouse SLX4 Is a Tumor Suppressor that Stimulates the Activity of the Nuclease XPF-ERCC1 in DNA Crosslink Repair [O] . Michael R.G. Hodskinson, Jan Silhan, Gerry P. Crossan, -1

机译：鼠标SLX4是一种肿瘤抑制因子可刺激DNA交联修复中的核酸酶XPF-ERCC1的活性。
8. Mouse SLX4 Is a Tumor Suppressor that Stimulates the Activity of the Nuclease XPF-ERCC1 in DNA Crosslink Repair [O] . Hodskinson Michael R. G., Silhan Jan, Crossan Gerry P., 2014

机译：鼠标SLX4是一种肿瘤抑制因子，可刺激DNA交联修复中的核酸酶XPF-ERCC1的活性。

Mouse SLX4 Is a Tumor Suppressor that Stimulates the Activity of the Nuclease XPF-ERCC1 in DNA Crosslink Repair

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