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Cell Rep. 2015 Mar 31;10(12):1957-66. doi: 10.1016/j.celrep.2015.03.038. Epub 2015 Mar 26.

UHRF1 contributes to DNA damage repair as a lesion recognition factor and nuclease scaffold.

Author information

1
Department of Experimental Radiation Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
2
Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
3
Department of Biochemistry, Baylor College of Medicine, Houston, TX 77030, USA.
4
Department of Genetics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
5
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.

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.

PMID:
25818288
PMCID:
PMC4748712
DOI:
10.1016/j.celrep.2015.03.038
[Indexed for MEDLINE]
Free PMC Article

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