Journal
EMBO JOURNAL
Volume 30, Issue 4, Pages 692-705Publisher
WILEY
DOI: 10.1038/emboj.2010.362
Keywords
BLM; Bloom's syndrome; FANCJ; Fanconi anemia; helicase
Categories
Funding
- NIH
- National Institute on Aging
- Cancer Research UK
- Fanconi Anemia Research Fund
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Bloom's syndrome (BS) and Fanconi anemia (FA) are autosomal recessive disorders characterized by cancer and chromosomal instability. BS and FA group J arise from mutations in the BLM and FANCJ genes, respectively, which encode DNA helicases. In this work, FANCJ and BLM were found to interact physically and functionally in human cells and co-localize to nuclear foci in response to replication stress. The cellular level of BLM is strongly dependent upon FANCJ, and BLM is degraded by a proteasome-mediated pathway when FANCJ is depleted. FANCJ-deficient cells display increased sister chromatid exchange and sensitivity to replication stress. Expression of a FANCJ C-terminal fragment that interacts with BLM exerted a dominant negative effect on hydroxyurea resistance by interfering with the FANCJ-BLM interaction. FANCJ and BLM synergistically unwound a DNA duplex substrate with sugar phosphate backbone discontinuity, but not an 'undamaged' duplex. Collectively, the results suggest that FANCJ catalytic activity and its effect on BLM protein stability contribute to preservation of genomic stability and a normal response to replication stress. The EMBO Journal (2011) 30, 692-705. doi:10.1038/emboj.2010.362; Published online 14 January 2011
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