UHRF1作为一种损伤识别因子和核酸酶支架，有助于DNA损伤修复。
UHRF1 contributes to DNA damage repair as a lesion recognition factor and nuclease scaffold.
作者信息
Tian Yanyan, Paramasivam Manikandan, Ghosal Gargi, Chen Ding, Shen Xi, Huang Yaling, Akhter Shamima, Legerski Randy, Chen Junjie, Seidman Michael M, Qin Jun, Li Lei
机构信息
Department of Experimental Radiation Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
出版信息
Cell Rep. 2015 Mar 31;10(12):1957-66. doi: 10.1016/j.celrep.2015.03.038. Epub 2015 Mar 26.
We identified ubiquitin-like with PHD and RING finger domain 1 (UHRF1) as a binding factor for DNA interstrand crosslink (ICL) lesions through affinity purification of ICL-recognition activities. UHRF1 is recruited to DNA lesions in vivo and binds directly to ICL-containing DNA. UHRF1-deficient cells display increased sensitivity to a variety of DNA damages. We found that loss of UHRF1 led to retarded lesion processing and reduced recruitment of ICL repair nucleases to the site of DNA damage. UHRF1 interacts physically with both ERCC1 and MUS81, two nucleases involved in the repair of ICL lesions. Depletion of both UHRF1 and components of the Fanconi anemia (FA) pathway resulted in increased DNA damage sensitivity compared to defect of each mechanism alone. These results suggest that UHRF1 promotes recruitment of lesion-processing activities via its affinity to recognize DNA damage and functions as a nuclease recruitment scaffold in parallel to the FA pathway.
我们通过对DNA链间交联（ICL）损伤识别活性进行亲和纯化，鉴定出含PHD和RING指结构域1的泛素样蛋白（UHRF1）作为DNA链间交联损伤的结合因子。UHRF1在体内被招募至DNA损伤处，并直接结合含ICL的DNA。UHRF1缺陷型细胞对多种DNA损伤表现出更高的敏感性。我们发现，UHRF1的缺失导致损伤处理延迟，并减少了ICL修复核酸酶向DNA损伤位点的募集。UHRF1与参与ICL损伤修复的两种核酸酶ERCC1和MUS81发生物理相互作用。与单独缺失每种机制相比，同时缺失UHRF1和范可尼贫血（FA）途径的组分导致对DNA损伤的敏感性增加。这些结果表明，UHRF1通过其识别DNA损伤的亲和力促进损伤处理活性的募集，并作为一种核酸酶募集支架，与FA途径并行发挥作用。
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