title: UHRF1 contributes to DNA damage repair as a lesion recognition factor and nuclease scaffold.
abstract: 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.
authors.affiliation: Department of Experimental Radiation Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Manikandan
authors.initials: M
authors.lastname: Paramasivam
authors.affiliation: Department of Experimental Radiation Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Gargi
authors.initials: G
authors.lastname: Ghosal
authors.affiliation: Department of Biochemistry, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ding
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Experimental Radiation Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Experimental Radiation Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yaling
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Genetics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Shamima
authors.initials: S
authors.lastname: Akhter
authors.affiliation: Department of Genetics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Randy
authors.initials: R
authors.lastname: Legerski
authors.affiliation: Department of Experimental Radiation Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Junjie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Seidman
authors.affiliation: Department of Biochemistry, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
authors.affiliation: Department of Experimental Radiation Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Genetics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: leili@mdanderson.org.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
mesh_terms: D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology*; D004720:Endonucleases / Q000378:metabolism; D005199:Fanconi Anemia / Q000235:genetics; D006801:Humans; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D025801:Ubiquitin; D004247:DNA; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases; D004720:Endonucleases
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