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Nucleic Acids Research Advance Access originally published online on August 4, 2009
Nucleic Acids Research 2009 37(17):5737-5748; doi:10.1093/nar/gkp632
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Nucleic Acids Research, 2009, Vol. 37, No. 17 5737-5748
© 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

Repair of gaps opposite lesions by homologous recombination in mammalian cells

Sheera Adar1, Lior Izhar1, Ayal Hendel1, Nicholas Geacintov2 and Zvi Livneh1,*

1Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel and 2Chemistry Department, New York University, New York, NY 1003-5180, USA

*To whom correspondence should be addressed. Tel: +972 8 934 3203; Fax: +972 8 934 4169; Email: zvi.livneh{at}weizmann.ac.il

Received April 13, 2009. Revised June 29, 2009. Accepted July 15, 2009.

Damages in the DNA template inhibit the progression of replication, which may cause single-stranded gaps. Such situations can be tolerated by translesion DNA synthesis (TLS), or by homology-dependent repair (HDR), which is based on transfer or copying of the missing information from the replicated sister chromatid. Whereas it is well established that TLS plays an important role in DNA damage tolerance in mammalian cells, it is unknown whether HDR operates in this process. Using a newly developed plasmid-based assay that distinguishes between the three mechanisms of DNA damage tolerance, we found that mammalian cells can efficiently utilize HDR to repair DNA gaps opposite an abasic site or benzo[a]pyrene adduct. The majority of these events occurred by a physical strand transfer (homologous recombination repair; HRR), rather than a template switch mechanism. Furthermore, cells deficient in either the human RAD51 recombination protein or NBS1, but not Rad18, exhibited decreased gap repair through HDR, indicating a role for these proteins in DNA damage tolerance. To our knowledge, this is the first direct evidence of gap-lesion repair via HDR in mammalian cells, providing further molecular insight into the potential activity of HDR in overcoming replication obstacles and maintaining genome stability.


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