MUS81 generates a subset of MLH1-MLH3-independent crossovers in mammalian meiosis

J. Kim Holloway, James Booth, Winfried Edelmann, Clare H. McGowan, Paula E. Cohen

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere1000186
JournalPLoS Genetics
Volume4
Issue number9
DOIs
StatePublished - Sep 2008

Fingerprint

Meiosis
meiosis
chiasmata
pachytene stage
Spermatocytes
spermatocytes
animal
Genomic Instability
Endonucleases
mice
crossover interference
somatic cells
sperm
defect
Spermatozoa
Testis
Mammals
chromosome
testes
animals

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

MUS81 generates a subset of MLH1-MLH3-independent crossovers in mammalian meiosis. / Holloway, J. Kim; Booth, James; Edelmann, Winfried; McGowan, Clare H.; Cohen, Paula E.

In: PLoS Genetics, Vol. 4, No. 9, e1000186, 09.2008.

Research output: Contribution to journalArticle

Holloway, J. Kim ; Booth, James ; Edelmann, Winfried ; McGowan, Clare H. ; Cohen, Paula E. / MUS81 generates a subset of MLH1-MLH3-independent crossovers in mammalian meiosis. In: PLoS Genetics. 2008 ; Vol. 4, No. 9.
@article{81e877aa5694436f8350c41bc41ed990,
title = "MUS81 generates a subset of MLH1-MLH3-independent crossovers in mammalian meiosis",
abstract = "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.",
author = "Holloway, {J. Kim} and James Booth and Winfried Edelmann and McGowan, {Clare H.} and Cohen, {Paula E.}",
year = "2008",
month = "9",
doi = "10.1371/journal.pgen.1000186",
language = "English (US)",
volume = "4",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "9",

}

TY - JOUR

T1 - MUS81 generates a subset of MLH1-MLH3-independent crossovers in mammalian meiosis

AU - Holloway, J. Kim

AU - Booth, James

AU - Edelmann, Winfried

AU - McGowan, Clare H.

AU - Cohen, Paula E.

PY - 2008/9

Y1 - 2008/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=52949098362&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=52949098362&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1000186

DO - 10.1371/journal.pgen.1000186

M3 - Article

VL - 4

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 9

M1 - e1000186

ER -