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Fanconi anaemia and the repair of Watson and Crick DNA crosslinks

Abstract

The function of Fanconi anaemia proteins is to maintain genomic stability. Their main role is in the repair of DNA interstrand crosslinks, which, by covalently binding the Watson and the Crick strands of DNA, impede replication and transcription. Inappropriate repair of interstrand crosslinks causes genomic instability, leading to cancer; conversely, the toxicity of crosslinking agents makes them a powerful chemotherapeutic. Fanconi anaemia proteins can promote stem-cell function, prevent tumorigenesis, stabilize replication forks and inhibit inaccurate repair. Recent advances have identified endogenous aldehydes as possible culprits of DNA damage that may induce the phenotypes seen in patients with Fanconi anaemia.

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Figure 1: The Fanconi anaemia pathway and interstrand crosslink repair.
Figure 2: The diverse functions of the Fanconi anaemia pathway.

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Acknowledgements

We thank A. Auerbach, S. Gregg, E. Garner, Y. Kim, S. Thongthip and A. Wang for their comments. Work in our laboratory is supported by the Burroughs Wellcome Fund Career Award for Medical Scientists, the Starr Center Consortium grant, and by grant number 8 UL1 TR000043 from the National Center for Research Resources and the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health. A.S. is a Rita Allen Foundation, Irma T. Hirschl, Alexandrine and Alexander Sinsheimer Foundation scholar, and is a recipient of the Doris Duke Clinical Scientist Development Award. M.C.K. is supported by an American Cancer Society-J.T.Tai postdoctoral fellowship.

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Kottemann, M., Smogorzewska, A. Fanconi anaemia and the repair of Watson and Crick DNA crosslinks. Nature 493, 356–363 (2013). https://doi.org/10.1038/nature11863

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