Human Molecular Genetics Advance Access originally published online on April 13, 2005
Human Molecular Genetics 2005 14(10):1351-1365; doi:10.1093/hmg/ddi145
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Intra-nuclear trafficking of the BLM helicase to DNA damage-induced foci is regulated by SUMO modification
1Laboratory of Cancer Susceptibility, Department of Medicine, Cell Biology Program and 2Cytogenetics Core Facility, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA and 3Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, USA
* To whom correspondence should be addressed at: Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. Tel: +1 2126397183; Fax: +1 2127173571; Email: ellisn{at}mskcc.org
Received January 25, 2005; Revised March 21, 2005; Accepted March 30, 2005
The Bloom syndrome gene, BLM, encodes a RecQ DNA helicase that when absent from the cell results in genomic instability and cancer predisposition. We show here that BLM is a substrate for small ubiquitin-like modifier (SUMO) modification, with lysines at K317, K331, K334 and K347 being preferred sites of modification. Unlike normal BLM, a double mutant BLM protein with lysine to arginine substitutions at residues 317 and 331 was not modified by SUMO, and it failed to localize efficiently to the PML nuclear bodies. Rather, double mutant BLM protein induced the formation of DNA damage-induced foci (DDI) that contained BRCA1 protein and phosphorylated histone H2AX. Double mutant BLM only partially complemented the genomic instability phenotypes of Bloom syndrome cells as assessed by sister-chromatid exchange and micronuclei formation assays. These results constitute evidence that BLM is a DNA damage sensor that signals the formation of DDI, and they establish SUMO modification as a negative regulator of BLM's signaling function.
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