MUS81 generates a subset of MLH1-MLH3-independent crossovers in mammalian meiosis.
Two eukaryotic pathways for processing double-strand breaks (DSBs) as crossovers have been described, one dependent on the MutL homologs Mlh1 and Mlh3, and the other on the structure-specific endonuclease Mus81. Mammalian MUS81 has been implicated in maintenance of genomic stability in somatic cells; however, little is known about its role during meiosis. Mus81-deficient mice were originally reported as being viable and fertile, with normal meiotic progression; however, a more detailed examination of meiotic progression in Mus81-null animals and WT controls reveals significant meiotic defects in the mutants. These include smaller testis size, a depletion of mature epididymal sperm, significantly upregulated accumulation of MLH1 on chromosomes from pachytene meiocytes in an interference-independent fashion, and a subset of meiotic DSBs that fail to be repaired. Interestingly, chiasmata numbers in spermatocytes from Mus81-/- animals are normal, suggesting additional integrated mechanisms controlling the two distinct crossover pathways. This study is the first in-depth analysis of meiotic progression in Mus81-nullizygous mice, and our results implicate the MUS81 pathway as a regulator of crossover frequency and placement in mammals.
Holloway
J Kim
JK
Department of Biomedical Sciences, Cornell University, Ithaca, New York, United States of America.
Booth
James
J
Edelmann
Winfried
W
McGowan
Clare H
CH
Cohen
Paula E
PE
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D003434:Crossing Over, Genetic; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004720:Endonucleases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D006720:Homozygote; D008297:Male; D008540:Meiosis / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D013076:Sperm Count; D013737:Testis / Q000166:cytology / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501485:Mlh1 protein, mouse; C492407:Mlh3 protein, mouse; D009687:Nuclear Proteins; D004720:Endonucleases; C498773:Mus81 protein, mouse; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins
Proc Natl Acad Sci U S A. 1999 May 11;96(10):5622-7
10318934
Plant J. 2008 Apr;54(1):152-62
18182028
Genes Dev. 2001 Oct 15;15(20):2730-40
11641278
Biol Reprod. 2003 Feb;68(2):628-34
12533428
Genetics. 1999 Apr;151(4):1569-79
10101178
J Cell Sci. 2007 Mar 1;120(Pt 5):731-6
17298983
Curr Biol. 2005 Apr 26;15(8):692-701
15854901
Cell. 2006 Dec 15;127(6):1167-78
17174892
Cell. 2001 Nov 16;107(4):537-48
11719193
Genes Dev. 2000 May 1;14(9):1085-97
10809667
Genetics. 2001 Jul;158(3):1013-25
11454751
J Biol Chem. 2001 Aug 10;276(32):30031-5
11325959
Genetics. 2001 Dec;159(4):1511-25
11779793
Cell. 2006 Jul 28;126(2):246-8
16873056
Chromosome Res. 1997 Feb;5(1):66-8
9088645
Mol Cell. 2003 Sep;12(3):761-74
14527420
Genetics. 2003 May;164(1):81-94
12750322
Genetics. 2008 Apr;178(4):1937-45
18430927
Am J Hum Genet. 2005 Jan;76(1):112-27
15558497
Biochem Soc Trans. 2001 May;29(Pt 2):196-201
11356153
Nature. 1998 Jan 22;391(6665):401-4
9450758
J Cell Biol. 1999 Oct 18;147(2):207-20
10525529
Mol Cell. 2002 Dec;10(6):1503-9
12504024
Genetics. 2003 Dec;165(4):2283-7
14704203
Microbiol Mol Biol Rev. 1999 Jun;63(2):349-404
10357855
Mol Cell. 2005 Nov 23;20(4):563-73
16307920
Cytogenet Genome Res. 2004;107(3-4):180-90
15467363
Science. 2004 Jun 18;304(5678):1822-6
15205536
Chromosoma. 1995 Nov;104(3):223-7
8529462
Am J Hum Genet. 2002 Dec;71(6):1353-68
12432495
Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3757-62
18310322
Nat Genet. 1999 Jan;21(1):123-7
9916805
Mol Cell Biol. 2005 Sep;25(17):7569-79
16107704
Cell. 1997 Feb 7;88(3):375-84
9039264
Genetics. 2002 Apr;160(4):1631-9
11973316
Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16887-92
12475932
Mol Cell. 2004 Aug 13;15(3):437-51
15304223
Mol Cell. 1998 Apr;1(5):697-705
9660953
Mol Cell. 1998 Apr;1(5):707-18
9660954
Dev Biol. 1994 Jun;163(2):331-40
8200475
J Cell Biol. 2005 Nov 7;171(3):447-58
16260499
EMBO J. 2008 May 7;27(9):1378-87
18388861
Genetics. 2004 Dec;168(4):1805-16
15611158
Chromosoma. 1995 Oct;104(1):19-28
7587590
EMBO J. 2007 Apr 4;26(7):1891-901
17363897
Cancer Res. 2005 Apr 1;65(7):2526-31
15805243
Nat Genet. 1996 Jul;13(3):336-42
8673133
Mol Cell Biol. 2000 Dec;20(23):8758-66
11073977
Plant Cell. 2007 Mar;19(3):862-76
17337626
J Biol Chem. 2003 Jul 4;278(27):25172-8
12721304
Curr Genet. 2005 Oct;48(4):213-25
16193328
Genes Dev. 2003 Mar 1;17(5):603-14
12629043
J Cell Biol. 1999 Jun 28;145(7):1395-406
10385520
Methods Mol Biol. 2004;262:239-53
14769966
J Cell Sci. 2000 Feb;113 ( Pt 4):663-72
10652259
Mol Cell Biol. 1997 Nov;17(11):6765-71
9343441
Cell. 2007 Jul 27;130(2):259-72
17662941
Mol Cell Biol. 2003 May;23(10):3487-96
12724407
Nat Genet. 2002 Aug;31(4):385-90
12091911
Genetics. 2001 Jan;157(1):103-18
11139495
Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9607-12
16766662