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肌醇六磷酸激酶 1 合成焦磷酸肌醇对于同源重组修复是必需的。

Inositol pyrophosphate synthesis by inositol hexakisphosphate kinase 1 is required for homologous recombination repair.

机构信息

Laboratory of Cell Signalling, Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500001, India.

出版信息

J Biol Chem. 2013 Feb 1;288(5):3312-21. doi: 10.1074/jbc.M112.396556. Epub 2012 Dec 19.

DOI:10.1074/jbc.M112.396556
PMID:23255604
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3561551/
Abstract

Inositol pyrophosphates, such as diphosphoinositol pentakisphosphate (IP(7)), are water-soluble inositol phosphates that contain high energy diphosphate moieties on the inositol ring. Inositol hexakisphosphate kinase 1 (IP6K1) participates in inositol pyrophosphate synthesis, converting inositol hexakisphosphate (IP(6)) to IP(7). In the present study, we show that mouse embryonic fibroblasts (MEFs) lacking IP6K1 exhibit impaired DNA damage repair via homologous recombination (HR). IP6K1 knock-out MEFs show decreased viability and reduced recovery after induction of DNA damage by the replication stress inducer, hydroxyurea, or the radiomimetic antibiotic, neocarzinostatin. Cells lacking IP6K1 arrest after genotoxic stress, and markers associated with DNA repair are recruited to DNA damage sites, indicating that HR repair is initiated in these cells. However, repair does not proceed to completion because these markers persist as nuclear foci long after drug removal. A fraction of IP6K1-deficient MEFs continues to proliferate despite the persistence of DNA damage, rendering the cells more susceptible to chromosomal aberrations. Expression of catalytically active but not inactive IP6K1 can restore the repair process in knock-out MEFs, implying that inositol pyrophosphates are required for HR-mediated repair. Our study therefore highlights inositol pyrophosphates as novel small molecule regulators of HR signaling in mammals.

摘要

肌醇六磷酸激酶 1（IP6K1）参与肌醇焦磷酸的合成，将肌醇六磷酸（IP（6））转化为 IP（7）。在本研究中，我们表明缺乏 IP6K1 的小鼠胚胎成纤维细胞（MEF）表现出同源重组（HR）受损的 DNA 损伤修复。IP6K1 敲除 MEF 在诱导复制应激诱导剂羟脲或放射模拟抗生素新制癌菌素引起的 DNA 损伤后，表现出活力降低和恢复减少。缺乏 IP6K1 的细胞在遗传毒性应激后停滞，并且与 DNA 修复相关的标记物被募集到 DNA 损伤部位，表明 HR 修复在这些细胞中被启动。然而，由于这些标记物在药物去除后很长时间仍然存在于核焦点中，因此修复不能完成。尽管存在 DNA 损伤，一部分缺乏 IP6K1 的 MEF 仍继续增殖，使细胞更容易发生染色体异常。表达具有催化活性但不具有非活性的 IP6K1 可以恢复敲除 MEF 中的修复过程，这意味着肌醇焦磷酸盐是 HR 介导的修复所必需的。因此，我们的研究强调了肌醇焦磷酸盐作为哺乳动物中 HR 信号的新型小分子调节剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a6c/3561551/56a3ce833110/zbc0091339350005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a6c/3561551/bdb1f455c7ce/zbc0091339350001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a6c/3561551/0228ed27e9ff/zbc0091339350002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a6c/3561551/bf8308091812/zbc0091339350003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a6c/3561551/13e092f1f3ac/zbc0091339350004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a6c/3561551/56a3ce833110/zbc0091339350005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a6c/3561551/bdb1f455c7ce/zbc0091339350001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a6c/3561551/0228ed27e9ff/zbc0091339350002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a6c/3561551/bf8308091812/zbc0091339350003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a6c/3561551/13e092f1f3ac/zbc0091339350004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a6c/3561551/56a3ce833110/zbc0091339350005.jpg

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