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Nucleic Acids Research Advance Access published online on May 21, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp365
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Genome Integrity, Repair and Replication

The Walker B motif in avian FANCM is required to limit sister chromatid exchanges but is dispensable for DNA crosslink repair

Ivan V. Rosado1, Wojciech Niedzwiedz1,2, Arno F. Alpi1 and Ketan J. Patel1,*

1MRC Laboratory of Molecular Biology, Hills Rd, Cambridge CB20QH and 2Department of Medical Oncology, Oxford University, Oxford OX3 9DS, UK

*To whom correspondence should be addressed. Email: kjp{at}mrc-1mb.cam.ac.uk

Received March 12, 2009. Revised April 22, 2009. Accepted April 23, 2009.

FANCM, the most highly conserved component of the Fanconi Anaemia (FA) pathway can resolve recombination intermediates and remodel synthetic replication forks. However, it is not known if these activities are relevant to how this conserved protein activates the FA pathway and promotes DNA crosslink repair. Here we use chicken DT40 cells to systematically dissect the function of the helicase and nuclease domains of FANCM. Our studies reveal that these domains contribute distinct roles in the tolerance of crosslinker, UV light and camptothecin-induced DNA damage. Although the complete helicase domain is critical for crosslink repair, a predicted inactivating mutation of the Walker B box domain has no impact on FA pathway associated functions. However, this mutation does result in elevated sister chromatid exchanges (SCE). Furthermore, our genetic dissection indicates that FANCM functions with the Blm helicase to suppress spontaneous SCE events. Overall our results lead us to reappraise the role of helicase domain associated activities of FANCM with respect to the activation of the FA pathway, crosslink repair and in the resolution of recombination intermediates.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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