Homology-directed Fanconi anemia pathway cross-link repair is dependent on DNA replication

Abstract

Homologous recombination (also termed homology-directed repair, HDR) is a major pathway for the repair of DNA interstrand cross-links (ICLs) in mammalian cells. Cells from individuals with Fanconi anemia (FA) are characterized by extreme ICL sensitivity, but their reported defect in HDR is mild. Here we examined ICL-induced HDR using a GFP reporter and observed a profound defect in ICL-induced HDR in FA cells, but only when the reporter could replicate.

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Figure 1: ICL induction of HDR in mammalian cells.
Figure 2: ICL- and DSB-induced HDR in mouse ES cell mutants.
Figure 3: FANCA-dependent, replication-coupled ICL-induced HDR.

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Acknowledgements

We thank K. Schlacher, J. LaRocque and L. Kass from the Jasin laboratory for comments on the manuscript. This work was supported by MFAG (My First AIRC Grant) 4765 from the Associazione Italiana per la Ricerca sul Cancro (M.B.), the Hecksher Foundation for Children (M.E.M.), the Byrne Fund (M.J.), and US National Institutes for Health grants P01CA94060 (M.E.M. and M.J.) and R01GM54668 (M.J.).

Author information

K.N. designed and performed experiments, analyzed data and assisted in manuscript preparation; F.C. performed experiments and analyzed data; L.P. prepared the ICL-only substrates; C.G. supervised L.P. and assisted in manuscript preparation; M.E.M. provide supervision, analyzed data and assisted in manuscript preparation; M.B. supervised F.C. and contributed to data analysis; E.B. designed experiments and assisted in manuscript preparation; M.J. designed the experiments, supervised the project and wrote the manuscript.

Correspondence to Maria Jasin.

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The authors declare no competing financial interests.

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Supplementary Methods, Supplementary Figures 1–4 and Supplementary Table 1 (PDF 756 kb)

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Nakanishi, K., Cavallo, F., Perrouault, L. et al. Homology-directed Fanconi anemia pathway cross-link repair is dependent on DNA replication. Nat Struct Mol Biol 18, 500–503 (2011) doi:10.1038/nsmb.2029

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