Interaction between the helicases genetically linked to Fanconi anemia group J and Bloom's syndrome.
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.
Laboratory of Molecular Gerontology, National Institute on Aging, NIH, NIH Biomedical Research Center, Baltimore, MD 21224, USA.
Avvaru N
AN
Suhasini
Nina A
NA
Rawtani
Yuliang
Y
Wu
Joshua A
JA
Sommers
Sudha
S
Sharma
Georgina
G
Mosedale
Phillip S
PS
North
Sharon B
SB
Cantor
Ian D
ID
Hickson
Robert M
RM
Brosh
D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D001816:Bloom Syndrome / Q000235:genetics*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D004261:DNA Replication / Q000235:genetics / Q000502:physiology; D005199:Fanconi Anemia / Q000235:genetics*; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics / Q000378:metabolism*; D042822:Genomic Instability / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007313:Insecta; D011485:Protein Binding / Q000502:physiology; D025941:Protein Interaction Mapping; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution
C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; C097151:Bloom syndrome protein; D004265:DNA Helicases; D053484:RecQ Helicases
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