Topo IIIalpha and BLM act within the Fanconi anemia pathway in response to DNA-crosslinking agents

Hemphill, A.W.; Akkari, Y.; Newell, A.H.; Schultz, R.A.; Grompe, M.; North, P.S.; Hickson, I.D.; Jakobs, P.M.; Rennie, S.; Pauw, D.; Hejna, J.; Olson, S.B.; Moses, R.E. (2009). Topo IIIalpha and BLM act within the Fanconi anemia pathway in response to DNA-crosslinking agents. Cytogenetic and genome research, 125(3), pp. 165-75. Basel: Karger 10.1159/000230001

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Parasitology

UniBE Contributor:

Hemphill, Andrew

ISSN:

1424-8581

Publisher:

Karger

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 15:25

Last Modified:

17 Mar 2015 22:53

Publisher DOI:

10.1159/000230001

Web of Science ID:

000269572100001

URI:

https://boris.unibe.ch/id/eprint/38339 (FactScience: 221174)

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