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Nucleic Acids Research Advance Access originally published online on December 4, 2008
Nucleic Acids Research 2009 37(2):482-492; doi:10.1093/nar/gkn957
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Nucleic Acids Research, 2009, Vol. 37, No. 2 482-492
© 2008 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

XLF-Cernunnos promotes DNA ligase IV–XRCC4 re-adenylation following ligation

Enriqueta Riballo, Lisa Woodbine, Thomas Stiff, Sarah A. Walker, Aaron A. Goodarzi and Penny A. Jeggo*

Genome Damage and Stability Centre, University of Sussex, East Sussex, BN1 9RQ, UK

*To whom correspondence should be addressed. Tel: +44 1273 678 482; Fax: +44 1273 678 121; Email: p.a.jeggo{at}sussex.ac.uk

Received October 14, 2008. Revised November 7, 2008. Accepted November 11, 2008.

XLF-Cernunnos (XLF) is a component of the DNA ligase IV–XRCC4 (LX) complex, which functions during DNA non-homologous end joining (NHEJ). Here, we use biochemical and cellular approaches to probe the impact of XLF on LX activities. We show that XLF stimulates adenylation of LX complexes de-adenylated by pyrophosphate or following LX decharging during ligation. XLF enhances LX ligation activity in an ATP-independent and dependent manner. ATP-independent stimulation can be attributed to enhanced end-bridging. Whilst ATP alone fails to stimulate LX ligation activity, addition of XLF and ATP promotes ligation in a manner consistent with XLF-stimulated readenylation linked to ligation. We show that XLF is a weakly bound partner of the tightly associated LX complex and, unlike XRCC4, is dispensable for LX stability. 2BN cells, which have little, if any, residual XLF activity, show a 3-fold decreased ability to repair DNA double strand breaks covering a range of complexity. These findings strongly suggest that XLF is not essential for NHEJ but promotes LX adenylation and hence ligation. We propose a model in which XLF, by in situ recharging DNA ligase IV after the first ligation event, promotes double stranded ligation by a single LX complex.


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