Trends in Cell Biology
ReviewCheckpoint mechanisms: the puppet masters of meiotic prophase
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
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