title: E-type cyclins modulate telomere integrity in mammalian male meiosis.
abstract: We have shown that E-type cyclins are key regulators of mammalian male meiosis. Depletion of cyclin E2 reduced fertility in male mice due to meiotic defects, involving abnormal pairing and synapsis, unrepaired DNA, and loss of telomere structure. These defects were exacerbated by additional loss of cyclin E1, and complete absence of both E-type cyclins produces a meiotic catastrophe. Here, we investigated the involvement of E-type cyclins in maintaining telomere integrity in male meiosis. Spermatocytes lacking cyclin E2 and one E1 allele (E1+/-E2-/-) displayed a high rate of telomere abnormalities but can progress to pachytene and diplotene stages. We show that their telomeres exhibited an aberrant DNA damage repair response during pachynema and that the shelterin complex proteins TRF2 and RAP2 were significantly decreased in the proximal telomeres. Moreover, the insufficient level of these proteins correlated with an increase of γ-H2AX foci in the affected telomeres and resulted in telomere associations involving TRF1 and telomere detachment in later prophase-I stages. These results suggest that E-type cyclins are key modulators of telomere integrity during meiosis by, at least in part, maintaining the balance of shelterin complex proteins, and uncover a novel role of E-type cyclins in regulating chromosome structure during male meiosis.
authors.affiliation: Department of Genetics & Development, Columbia University Medical Center, New York, NY, 10032, USA.
authors.forename: Marcia
authors.initials: M
authors.lastname: Manterola
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Sicinski
authors.affiliation: Department of Genetics & Development, Columbia University Medical Center, New York, NY, 10032, USA. djw3@columbia.edu.|Obstetrics & Gynecology, Columbia University Medical Center, New York, NY, 10032, USA. djw3@columbia.edu.|Institute of Human Nutrition, Columbia University Medical Center, New York, NY, 10032, USA. djw3@columbia.edu.
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Wolgemuth
mesh_terms: D000818:Animals; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D008297:Male; D008540:Meiosis; D051379:Mice; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D049471:Pachytene Stage; D013090:Spermatocytes / Q000166:cytology* / Q000378:metabolism; D016615:Telomere / Q000235:genetics / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D020668:rap GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C503689:Ccne2 protein, mouse; D019927:Cyclin E; D016213:Cyclins; D015513:Oncogene Proteins; C534796:TRF2 protein, mouse; D035341:Telomeric Repeat Binding Protein 2; C568314:cyclin E1, mouse; C492137:Rap2a protein, mouse; D020668:rap GTP-Binding Proteins
keywords: Cyclin E1; Cyclin E2; E-type cyclins; Meiosis; Meiosis control; Shelterin complex; TRF1; TRF2; Telomere; Telomere integrity