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BOR - Papers in Press, published online ahead of print November 21, 2007.
Biol Reprod 2007, 10.1095/biolreprod.107.064162
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BIOLOGY OF REPRODUCTION 78, 324–332 (2008)
DOI: 10.1095/biolreprod.107.064162
© 2008 by the Society for the Study of Reproduction, Inc.

DNA Damage Response During Chromatin Remodeling in Elongating Spermatids of Mice1

Frédéric Leduc , Vincent Maquennehan , Geneviève Bikond Nkoma , and Guylain Boissonneault  2

Département de Biochimie, Faculté de Médecine et Sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4

ABSTRACT

A precise packaging of the paternal genome during spermiogenesis is essential for fertilization and embryogenesis. Most of the nucleosomal DNA supercoiling must be eliminated in elongating spermatids (ES), and transient DNA strand breaks are observed that facilitate the process. Topoisomerases have been considered as ideal candidates for the removal of DNA supercoiling, but their catalytic activity, in the context of such a major chromatin remodeling, entails genetic risks. Using immunofluorescence, we confirmed that topoisomerase II beta (TOP2B) is the type II topoisomerase present in ES between steps 9 and 13. Interestingly, the detection of TOP2B was found coincident with detection of tyrosyl-DNA phosphodiesterase 1 (TDP1), an enzyme known to resolve topoisomerase-mediated DNA damage. The presence of gamma-H2AX (also known as H2AFX) coincident with DNA strand breakage was also confirmed at these steps and indicates that a DNA damage response is triggered. Active DNA repair in ES was demonstrated using a fluorescent in situ DNA polymerase activity assay on squash preparations of staged tubules. In the context of haploid spermatids, any unresolved double-strand breaks, resulting from a failure in the rejoining process of TOP2B, must likely rely on the error-prone nonhomologous end joining, because homologous recombination cannot proceed in the absence of a sister chromatid. Because this process is part of the normal developmental program of the spermatids, dramatic consequences for the genomic integrity of the developing male gamete may arise should any alteration in the process occur.

chromatin, DNA repair, H2AX, spermiogenesis, topoisomerase

FOOTNOTES

1Supported by the Canadian Institutes of Health Research (grant MOP-74500) to G.B. Part of this work was presented at the 53rd annual meeting of the Canadian Fertility and Andrology Society in Halifax, Nova Scotia, Canada, September 26–29, 2007.

Correspondence: 2Guylain Boissonneault, Département de Biochimie, Faculté de Médicine et Sciences de la santé, Université de Sherbrooke, 3001 12ième Ave Nord, Sherbrooke, Québec, Canada J1H 5N4. FAX: 819 564 5340; e-mail: guylain.boissonneault{at}usherbrooke.ca






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Copyright © 2008 by the Society for the Study of Reproduction.