Open AccessTopo IIIα and BLM Act within the Fanconi Anemia Pathway in Response to DNA-Crosslinking Agents
Author(s) -
Aaron Hemphill,
Yassmine Akkari,
Amy Hanlon Newell,
Roger A. Schultz,
Markus Grompe,
Phillip North,
Ian D. Hickson,
Petra M. Jakobs,
Scott Rennie,
Daniel Pauw,
James Hejna,
Susan B. Olson,
Robb E. Moses
Publication year - 2009
Publication title -
cytogenetic and genome research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.571
H-Index - 88
ISSN - 1424-8581
DOI - 10.1159/000230001
Subject(s) - fanconi anemia , fancd2 , biology , bloom syndrome , topoisomerase , sister chromatid exchange , chromosome instability , sister chromatids , microbiology and biotechnology , genome instability , dna damage , dna , genetics , dna repair , chromosome , gene , rna , helicase
The Bloom protein (BLM) and Topoisomerase IIIalpha are found in association with proteins of the Fanconi anemia (FA) pathway, a disorder manifesting increased cellular sensitivity to DNA crosslinking agents. In order to determine if the association reflects a functional interaction for the maintenance of genome stability, we have analyzed the effects of siRNA-mediated depletion of the proteins in human cells. Depletion of Topoisomerase IIIalpha or BLM leads to increased radial formation, as is seen in FA. BLM and Topoisomerase IIIalpha are epistatic to the FA pathway for suppression of radial formation in response to DNA interstrand crosslinks since depletion of either of them in FA cells does not increase radial formation. Depletion of Topoisomerase IIIalpha or BLM also causes an increase in sister chromatid exchanges, as is seen in Bloom syndrome cells. Human Fanconi anemia cells, however, do not demonstrate increased sister chromatid exchanges, separating this response from radial formation. Primary cell lines from mice defective in both Blm and Fancd2 have the same interstrand crosslink-induced genome instability as cells from mice deficient in the Fancd2 protein alone. These observations demonstrate that the association of BLM and Topoisomerase IIIalpha with Fanconi proteins is a functional one, delineating a BLM-Topoisomerase IIIalpha-Fanconi pathway that is critical for suppression of chromosome radial formation.