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PMID: 12591952 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Infertility and aneuploidy in mice lacking a type IA DNA topoisomerase III beta.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 100 ·No. 5 ·2003-03-04 ·Pages 2526-31

Kwan KY, Moens PB, Wang JC

Abstract

We report that disruption of the mouse TOP3 beta gene encoding DNA topoisomerase III beta, one of the two mammalian type IA DNA topoisomerases, leads to a progressive reduction in fecundity. The litter size in crosses of top3 beta(-/-) mice decreases over time and through successive generations, and this decrease seems to reflect embryonic death rather than impaired fertilization. These observations are suggestive of a gradual accumulation of chromosomal defects in germ cells lacking DNA topoisomerase III beta, and this interpretation is supported by the observation of a high incidence of aneuploidy in the spermatocytes of infertile top3 beta(-/-) males. Cytogenetic examination of spermatocytes of wild-type mice also indicates that DNA topoisomerase III beta becomes prominently associated with the asynaptic regions of the XY bivalents during pachytene, and that there is a time lag between the appearance of chromosome-bound DNA topoisomerase III beta and Rad51, a protein known to be involved in an early step of homologous recombination. We interpret these findings, together with the known mechanistic characteristics of different subfamilies of DNA topoisomerases, in terms of a specific role of a type IA DNA topoisomerase in the resolution of meiotic double-Holliday junctions without crossing over. This interpretation is most likely applicable to mitotic cells as well and can explain the universal presence of at least one type IA DNA topoisomerase in all organisms.

MeSH Terms
Aneuploidy Animals Chromosome Aberrations Crosses, Genetic DNA Topoisomerases, Type I/genetics,physiology DNA-Binding Proteins/metabolism Female Genotype In Situ Hybridization, Fluorescence Infertility Isoenzymes/genetics,physiology Male Meiosis Metaphase Mice Mice, Inbred C57BL Microscopy, Fluorescence Rad51 Recombinase Recombination, Genetic Spermatocytes/cytology Time Factors
Chemicals
DNA-Binding Proteins Isoenzymes Rad51 Recombinase Rad51 protein, mouse DNA Topoisomerases, Type I
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Kwan Kelvin Y
Department of Molecular and Cellular Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA.
Moens Peter B
Wang James C
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0437998100
Published
2003-03-04
Epub
2003-00-18
Pages
2526-31
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC151374
Subset
IM
Grants
NIGMS NIH HHS · R01 GM024544 · United States
NIGMS NIH HHS · R37 GM024544 · United States
NCI NIH HHS · CA47958 · United States
NIGMS NIH HHS · GM24544 · United States
External Links
PubMed source DOI: 10.1073/pnas.0437998100 PMC Full Text View journal details
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