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Nucleic Acids Research Advance Access originally published online on June 3, 2008
Nucleic Acids Research 2008 36(12):4047-4056; doi:10.1093/nar/gkn341
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Nucleic Acids Research, 2008, Vol. 36, No. 12 4047-4056
© 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.

Molecular Biology

Alkylation damage causes MMR-dependent chromosomal instability in vertebrate embryos

Harma Feitsma, Alper Akay and Edwin Cuppen*

Hubrecht Institute, Royal Academy of Arts and Sciences & University Medical Centre Utrecht, Cancer Genomics Center, 3584 CT, Utrecht, The Netherlands

*To whom correspondence should be addressed. Tel: +31 30 2121969; Fax: +31 30 2516554; Email: e.cuppen{at}niob.knaw.nl

Received January 21, 2008. Revised April 15, 2008. Accepted May 12, 2008.

SN1-type alkylating agents, like N-methyl-N-nitrosourea (MNU) and N-ethyl-N-nitrosourea (ENU), are potent mutagens. Exposure to alkylating agents gives rise to O6-alkylguanine, a modified base that is recognized by DNA mismatch repair (MMR) proteins but is not repairable, resulting in replication fork stalling and cell death. We used a somatic mutation detection assay to study the in vivo effects of alkylation damage on lethality and mutation frequency in developing zebrafish embryos. Consistent with the damage-sensing role of the MMR system, mutant embryos lacking the MMR enzyme MSH6 displayed lower lethality than wild-type embryos after exposure to ENU and MNU. In line with this, alkylation-induced somatic mutation frequencies were found to be higher in wild-type embryos than in the msh6 loss-of-function mutants. These mutations were found to be chromosomal aberrations that may be caused by chromosomal breaks that arise from stalled replication forks. As these chromosomal breaks arise at replication, they are not expected to be repaired by non-homologous end joining. Indeed, Ku70 loss-of-function mutants were found to be equally sensitive to ENU as wild-type embryos. Taken together, our results suggest that in vivo alkylation damage results in chromosomal instability and cell death due to aberrantly processed MMR-induced stalled replication forks.


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