Mutation of the ATPase domain of mutS homolog-5 (MSH5) reveals a requirement for a functional MutSG complex for all crossovers in mammalian meiosis

Carolyn R. Milano, J. Kim Holloway, Yongwei Zhang, Bo Jin, Cameron Smith, Aviv Bergman, Winfried Edelmann, Paula E. Cohen

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

During meiosis, induction of DNA double strand breaks (DSB) leads to recombination between homologous chromosomes, resulting in crossovers (CO) and non-crossovers (NCO). In the mouse, only 10% of DSBs resolve as COs, mostly through a class I pathway dependent on MutSg (MSH4/ MSH5) and MutLg (MLH1/MLH3), the latter representing the ultimate marker of these CO events. A second Class II CO pathway accounts for only a few COs, but is not thought to involve MutSg/ MutLg, and is instead dependent on MUS81-EME1. For class I events, loading of MutLg is thought to be dependent on MutSg, however MutSg loads very early in prophase I at a frequency that far exceeds the final number of class I COs. Moreover, loss of MutSg in mouse results in apoptosis before CO formation, preventing the analysis of its CO function. We generated a mutation in the ATP binding domain of Msh5 (Msh5GA). While this mutation was not expected to affect MutSg complex formation, MutSg foci do not accumulate during prophase I. However, most spermatocytes from Msh5GA/GA mice progress to late pachynema and beyond, considerably further than meiosis in Msh52/2 animals. At pachynema, Msh5GA/GA spermatocytes show persistent DSBs, incomplete homolog pairing, and fail to accumulate MutLg. Unexpectedly, Msh5GA/GA diakinesis-staged spermatocytes have no chiasmata at all from any CO pathway, indicating that a functional MutSg complex is critical for all CO events regardless of their mechanism of generation.

Original languageEnglish (US)
Pages (from-to)1839-1850
Number of pages12
JournalG3: Genes, Genomes, Genetics
Volume9
Issue number6
DOIs
StatePublished - Jan 1 2019

Fingerprint

Meiotic Prophase I
Spermatocytes
Meiosis
Pachytene Stage
Adenosine Triphosphatases
Mutation
Double-Stranded DNA Breaks
Genetic Recombination
Chromosomes
Adenosine Triphosphate
Apoptosis
1,2-di-(4-sulfamidophenyl)-4-butylpyrazolidine-3,5-dione

Keywords

  • Crossing over
  • Crossover
  • Designation
  • Homologous
  • Meiosis
  • Mouse
  • MutS homolog
  • Prophase I
  • Recombination

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Mutation of the ATPase domain of mutS homolog-5 (MSH5) reveals a requirement for a functional MutSG complex for all crossovers in mammalian meiosis. / Milano, Carolyn R.; Kim Holloway, J.; Zhang, Yongwei; Jin, Bo; Smith, Cameron; Bergman, Aviv; Edelmann, Winfried; Cohen, Paula E.

In: G3: Genes, Genomes, Genetics, Vol. 9, No. 6, 01.01.2019, p. 1839-1850.

Research output: Contribution to journalArticle

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abstract = "During meiosis, induction of DNA double strand breaks (DSB) leads to recombination between homologous chromosomes, resulting in crossovers (CO) and non-crossovers (NCO). In the mouse, only 10{\%} of DSBs resolve as COs, mostly through a class I pathway dependent on MutSg (MSH4/ MSH5) and MutLg (MLH1/MLH3), the latter representing the ultimate marker of these CO events. A second Class II CO pathway accounts for only a few COs, but is not thought to involve MutSg/ MutLg, and is instead dependent on MUS81-EME1. For class I events, loading of MutLg is thought to be dependent on MutSg, however MutSg loads very early in prophase I at a frequency that far exceeds the final number of class I COs. Moreover, loss of MutSg in mouse results in apoptosis before CO formation, preventing the analysis of its CO function. We generated a mutation in the ATP binding domain of Msh5 (Msh5GA). While this mutation was not expected to affect MutSg complex formation, MutSg foci do not accumulate during prophase I. However, most spermatocytes from Msh5GA/GA mice progress to late pachynema and beyond, considerably further than meiosis in Msh52/2 animals. At pachynema, Msh5GA/GA spermatocytes show persistent DSBs, incomplete homolog pairing, and fail to accumulate MutLg. Unexpectedly, Msh5GA/GA diakinesis-staged spermatocytes have no chiasmata at all from any CO pathway, indicating that a functional MutSg complex is critical for all CO events regardless of their mechanism of generation.",
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AU - Milano, Carolyn R.

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AU - Zhang, Yongwei

AU - Jin, Bo

AU - Smith, Cameron

AU - Bergman, Aviv

AU - Edelmann, Winfried

AU - Cohen, Paula E.

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