Originally published as Genetics Published Articles Ahead of Print on February 23, 2009.

Genetics, Vol. 182, 41-54, May 2009, Copyright © 2009
doi:10.1534/genetics.109.101683

Alternative Induction of Meiotic Recombination From Single-Base Lesions of DNA Deaminases

Siim Pauklin^*, Julia S. Burkert^*, Julie Martin, Fekret Osman, Sandra Weller, Simon J. Boulton, Matthew C. Whitby and Svend K. Petersen-Mahrt^*,1

^* DNA Editing Lab, DNA Damage Response Lab, Clare Hall Laboratories, Cancer Research UK, South Mimms EN6 3LD, United Kingdom, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom and INSERM U783, Faculté de Médicine Necker-Enfants Malades, 75730 Paris Cedex 15, France

¹ Corresponding author: London Research Institute, Clare Hall Laboratories, DNA Editing Lab, South Mimms EN6 3LD, United Kingdom.
E-mail: skpm{at}cancer.org.uk

Meiotic recombination enhances genetic diversity as well as ensures proper segregation of homologous chromosomes, requiring Spo11-initiated double-strand breaks (DSBs). DNA deaminases act on regions of single-stranded DNA and deaminate cytosine to uracil (dU). In the immunoglobulin locus, this lesion will initiate point mutations, gene conversion, and DNA recombination. To begin to delineate the effect of induced base lesions on meiosis, we analyzed the effect of expressing DNA deaminases (activation-induced deaminase, AID, and APOBEC3C) in germ cells. We show that meiotic dU:dG lesions can partially rescue a spo11 phenotype in yeast and worm. In rec12 Schizosaccharomyces pombe, AID expression increased proper chromosome segregation, thereby enhancing spore viability, and induced low-frequency meiotic crossovers. Expression of AID in the germ cells of Caenorhabditis elegans spo-11 induced meiotic RAD-51 foci formation and chromosomal bivalency and segregation, as well as an increase in viability. RNAi experiments showed that this rescue was dependent on uracil DNA-glycosylase (Ung). Furthermore, unlike ionizing radiation-induced spo-11 rescue, AID expression did not induce large numbers of DSBs during the rescue. This suggests that the products of DNA deamination and base excision repair, such as uracil, an abasic site, or a single-stranded nick, are sufficient to initiate and alter meiotic recombination in uni- and multicellular organisms.

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Genetics 2009 182: NP. [Full Text]  

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Online ISSN: 1943-2361  Print ISSN: 0016-6731
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