Review
Checkpoint mechanisms: the puppet masters of meiotic prophase

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The coordinated execution of cell cycle processes during meiosis is essential for the production of viable gametes and fertility. Coordination is particularly important during meiotic prophase, when nuclei undergo a dramatic reorganization that requires the precise choreography of chromosome movements, pairing interactions and DNA double-strand break (DSB) repair. Analysis of the underlying regulatory mechanisms has revealed crucial and widespread roles for DNA-damage checkpoint proteins, not only in cell cycle surveillance, but also in controlling many processes uniquely characteristic of meiosis. The resulting regulatory network uses checkpoint machinery to provide an integral coordinating mechanism during every meiotic division and enables cells to safely maintain an error-prone event such as DSB formation as an essential part of the meiotic program.

Section snippets

The coordination of meiosis

When cells divide, be it by mitosis to create two identical daughter cells, or by meiosis to create gametes with half the genome complement of the mother cell, they follow a highly choreographed program. This program involves the precise duplication of chromosomes and other cellular structures, their packaging and alignment with respect to the division plane and finally, their separation. For successful cell division, these processes must be carefully coordinated with one another. One way to

Operational definitions

Throughout this review, we use the term ‘checkpoint mechanism’ in its broadest sense, that is, a signaling mechanism that establishes dependencies between cell cycle events 1, 2. By this definition, the widely studied checkpoint responses to terminal chromosome damage (i.e. meiotic arrest and apoptosis) are a specialized function of the prophase checkpoint network. We reserve the use of ‘recombination checkpoint’ and ‘synapsis checkpoint’ to specifically refer to these terminal responses, in

Detecting DSBs

In most organisms, the initial detection of DSBs relies on two related and highly conserved kinases, ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related) 11, 12. Unprocessed DSBs are first sensed by ATM, which binds to DNA ends with the help of the MRE11/RAD50/NBS1 (MRN) complex. This leads to further processing of break ends and the recruitment and activation of ATR (Figure 2). ATR is recruited to DSBs by the presence of replication protein A (RPA)-coated single-stranded DNA

Arrest and eliminate

Activation of ATM/ATR by unrepaired (Spo11-induced) DSBs leads to a delay in meiotic progression in many organisms, similar to the effect of the mitotic DNA-damage checkpoint response. This response is called the recombination checkpoint or pachytene checkpoint, and might provide extra time to complete DSB repair before the meiotic divisions. It also provides an opportunity to cull meiotic cells unable to complete DSB repair through apoptosis 9, 10, 19. Interestingly, although the recombination

The DNA-damage checkpoint machinery regulates meiotic DSB repair

Signaling how meiotic DSBs are to be repaired is a widely conserved meiotic function of DNA-damage checkpoint proteins. As in the mitotic DNA-damage response, this signal only initiates once DSBs have formed 12, 14. In some cases, the role of the meiotic checkpoint machinery appears to be a relatively general activation of DNA-repair functions. For example, mice or plants lacking ATM are strongly defective in meiotic DSB repair 30, 31, 32. Similarly, in S. cerevisiae, ATR/ATM

HORMA-domain proteins: adaptors for meiotic checkpoint protein signaling

Proteins homologous to the Hop1 family of HORMA-domain proteins have emerged as key regulators of meiotic chromosome behavior in many organisms. These proteins harbor a protein-interaction domain of approximately 200 residues, whose function remains poorly understood [4], and are integral components of meiotic chromosomes. Notably, HORMA proteins often simultaneously govern multiple meiotic processes. For example, Hop1 in budding yeast not only controls repair bias, but also modulates DSB

Regulation of global chromosome dynamics

Signaling by the prophase checkpoint network also provides a direct link between DSB formation and chromosome dynamics. This control function is particularly evident in the case of organisms that require meiotic recombination initiation as a prerequisite for homologous chromosome synapsis, such as budding yeast, mammals and plants. It presumably aids the transition from early (often homology-independent) chromosomal interactions to bona fide homologous pairing associations. Homology-independent

DSB-independent signaling by the checkpoint machinery

DSB-activated ATM and/or ATR appear to play less prominent roles in regulating homologous chromosome pairing and/or SC assembly in organisms such as C. elegans and Drosophila, in which DSB formation, chromosome pairing and synapsis can occur independently of each other 66, 67. Interestingly, DSB-independent signals nevertheless activate checkpoint protein ‘modules’ that, in turn, play crucial roles in regulating meiotic chromosome dynamics in these organisms. Perhaps the best example of this is

The synapsis checkpoint

Certain defects in chromosome axis formation or aberrant SC assembly can trigger a delay in meiotic progression or apoptosis independently of DSB formation. This ‘synapsis checkpoint’ has been most clearly elucidated by studies in C. elegans and Drosophila, in which defects in homologous synapsis can be unambiguously assessed apart from defects in meiotic recombination 70, 71. Interestingly, despite its apparent DSB independence, the C. elegans synapsis checkpoint depends on some components of

Sex body formation

A specialized signaling response by the meiotic prophase checkpoint network, triggered by unpaired/unsynapsed chromosomes, might also underlie sex chromosome inactivation in the mouse. During mouse spermatogenesis, the X and Y chromosomes are sequestered from the autosomes, and form the transcriptionally repressed and condensed sex body [82], which requires histone H2AX 81, 83 and is characterized by abundant H2AX phosphorylation [82]. Moreover, the formation of robust γ-H2AX domains during

Conclusion

A large body of work accumulated over the past several years indicates that the role of DNA-damage checkpoint proteins in meiotic prophase is substantially more complex than simply providing a mechanism for quality control. Rather, the prophase checkpoint network appears to be employed as a major integrating principle of meiotic prophase, which both responds to errors and drives the coordinated progression of meiotic DSB repair, chromosome dynamics and homologous synapsis. Meiotic chromosome

References (89)

  • J.E. Falk

    A Mec1- and PP4-dependent checkpoint couples centromere pairing to meiotic recombination

    Dev. Cell

    (2010)
  • J.A. Carballo

    Phosphorylation of the axial element protein Hop1 by Mec1/Tel1 ensures meiotic interhomolog recombination

    Cell

    (2008)
  • H. Niu

    Regulation of meiotic recombination via Mek1-mediated Rad54 phosphorylation

    Mol. Cell

    (2009)
  • W. Goodyer

    HTP-3 links DSB formation with homolog pairing and crossing over during C. elegans meiosis

    Dev. Cell

    (2008)
  • A. Sato

    Cytoskeletal forces span the nuclear envelope to coordinate meiotic chromosome pairing and synapsis

    Cell

    (2009)
  • B. Liebe

    Mutations that affect meiosis in male mice influence the dynamics of the mid-preleptotene and bouquet stages

    Exp. Cell Res.

    (2006)
  • A.F. Dernburg

    Meiotic recombination in C. elegans initiates by a conserved mechanism and is dispensable for homologous chromosome synapsis

    Cell

    (1998)
  • A. Higashitani

    Caenorhabditis elegans Chk2-like gene is essential for meiosis but dispensable for DNA repair

    FEBS Lett.

    (2000)
  • A.M. Penkner

    Meiotic chromosome homology search involves modifications of the nuclear envelope protein Matefin/SUN-1

    Cell

    (2009)
  • A.J. MacQueen

    Chromosome sites play dual roles to establish homologous synapsis during meiosis in C. elegans

    Cell

    (2005)
  • P.A. San-Segundo et al.

    Pch2 links chromatin silencing to meiotic checkpoint control

    Cell

    (1999)
  • H.Y. Wu et al.

    Two distinct surveillance mechanisms monitor meiotic chromosome metabolism in budding yeast

    Curr. Biol.

    (2006)
  • O. Fernandez-Capetillo

    H2AX is required for chromatin remodeling and inactivation of sex chromosomes in male mouse meiosis

    Dev. Cell

    (2003)
  • J.M. Turner

    BRCA1, histone H2AX phosphorylation, and male meiotic sex chromosome inactivation

    Curr. Biol.

    (2004)
  • L.H. Hartwell et al.

    Checkpoints: controls that ensure the order of cell cycle events

    Science

    (1989)
  • S.J. Elledge

    Cell cycle checkpoints: preventing an identity crisis

    Science

    (1996)
  • R.S. Cha et al.

    ATR homolog Mec1 promotes fork progression, thus averting breaks in replication slow zones

    Science

    (2002)
  • A. Musacchio et al.

    The spindle-assembly checkpoint in space and time

    Nat. Rev. Mol. Cell. Biol.

    (2007)
  • S. Keeney et al.

    Initiation of meiotic recombination by formation of DNA double-strand breaks: mechanism and regulation

    Biochem. Soc. Trans.

    (2006)
  • W.D. Heyer

    Regulation of homologous recombination in eukaryotes

    Annu. Rev. Genet.

    (2010)
  • D. Zickler

    From early homologue recognition to synaptonemal complex formation

    Chromosoma

    (2006)
  • A. Hochwagen et al.

    Checking your breaks: surveillance mechanisms of meiotic recombination

    Curr. Biol.

    (2006)
  • J.C. Harrison et al.

    Surviving the breakup: the DNA damage checkpoint

    Annu. Rev. Genet.

    (2006)
  • P.S. Burgoyne

    The management of DNA double-strand breaks in mitotic G2, and in mammalian meiosis viewed from a mitotic G2 perspective

    Bioessays

    (2007)
  • J.A. Carballo et al.

    Meiotic roles of Mec1, a budding yeast homolog of mammalian ATR/ATM

    Chromosome Res.

    (2007)
  • H. Cartagena-Lirola

    Role of the Saccharomyces cerevisiae Rad53 checkpoint kinase in signaling double-strand breaks during the meiotic cell cycle

    Mol. Cell. Biol.

    (2008)
  • L.W. Thorne et al.

    Stage-specific effects of X-irradiation on yeast meiosis

    Genetics

    (1993)
  • A. Malkova

    HO endonuclease-induced recombination in yeast meiosis resembles Spo11-induced events

    Proc. Natl. Acad. Sci. U.S.A.

    (2000)
  • A.J. MacQueen et al.

    Nuclear reorganization and homologous chromosome pairing during meiotic prophase require C. elegans chk-2

    Genes Dev.

    (2001)
  • L. Perez-Hidalgo

    The fission yeast meiotic checkpoint kinase Mek1 regulates nuclear localization of Cdc25 by phosphorylation

    Cell Cycle

    (2008)
  • A. Sourirajan et al.

    Polo-like kinase Cdc5 drives exit from pachytene during budding yeast meiosis

    Genes Dev.

    (2008)
  • O.M. Lancaster

    The meiotic recombination checkpoint suppresses NHK-1 kinase to prevent reorganisation of the oocyte nucleus in Drosophila

    PLoS Genet.

    (2010)
  • F. Couteau

    Random chromosome segregation without meiotic arrest in both male and female meiocytes of a dmc1 mutant of Arabidopsis

    Plant Cell

    (1999)
  • M. Shimada

    The meiotic recombination checkpoint is regulated by checkpoint rad+ genes in fission yeast

    Embo J.

    (2002)
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