Interaction between the helicases genetically linked to Fanconi anemia group J and Bloom's syndrome

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Avvaru N Suhasini
  • Nina A Rawtani
  • Yuliang Wu
  • Joshua A Sommers
  • Sudha Sharma
  • Georgina Mosedale
  • Phillip S North
  • Sharon B Cantor
  • Hickson, Ian David
  • Robert M Brosh
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.
OriginalsprogEngelsk
TidsskriftE M B O Journal
Vol/bind30
Udgave nummer4
Sider (fra-til)692-705
Antal sider14
ISSN0261-4189
DOI
StatusUdgivet - 16 feb. 2011

ID: 33232342