br Mechanisms of homeostasis At face value homeostatic

Mechanisms of homeostasis At face value, homeostatic mechanisms may seem like nothing more than a simple balance between opposing forces; however, the ability of Mec1/Tel1 to each orchestrate both negative and positive regulation greatly complicates the system under consideration and argues against any form of linearity. The biological outcome of any signalling pathway can greatly vary in response to a number of things including the ways in which its components are spatially or temporally regulated, signal/stimulus strength, target abundance and phosphorylation efficiencies [58]. DSB ecopipam undoubtedly employs a similar array of methods to achieve balance between positive and negative regulation under multiple cellular contexts. As DSB formation is not reactivated as repair progresses and break levels fall, there must exist a point at which the influence of the discussed ATM/ATR-dependent mechanisms is diminished. Interestingly, homolog synapsis was recently shown to suppress DSB formation and represent a novel branch of regulation [59]. Thus, it may prove that the mechanisms discussed throughout constitute a first phase of regulation that ultimately ensures synapsis is achieved in those organisms whose synapsis is DSB-dependent. Consequently, the cell then enters the second phase where it effectively “hands-over” control to the mediators of synapsis-dependent regulation as well as Ndt80, priming the cell for chromosomal segregation. Indeed, formation of the synaptonemal complex as assayed via Zip1 (S. cerevisiae) and SYCP3 (mouse) staining, strongly correlates to loss of Hop1 and HORMAD1/2 respectively—loss that is dependent upon Pch2/TRIP13 [31], [60], [61]. Such observations highlight the ability of synapsis to remove a critical ATM/ATR substrate and its potential to initiate a “hand-over” between regulatory phases. The synaptonemal complex could thus be considered a “checkpoint” factor in its own right. However, whether or not synapsis-dependent feedback depends upon ATM/ATR is currently unknown and certainly cannot be ruled out.
Concluding remarks While detection of meiotic damage is assumingly identical to its mitotic counterpart, there has been an obvious adoption of meiosis-specific targets outside the scope of traditional ATM/ATR targets. Evolution of a meiotic DDR and a system to carefully regulate DSB formation likely reflects (i) the absolute requirement for cells to be able to stringently manage widespread, potentially fatal damage; (ii) the need to homeostatically buffer biological variability on a cell-to-cell basis and (iii) the ultimate purpose of meiosis: the exchange of genetic information. Indeed, as evidenced here, both Mec1- and Tel1-dependent systems safeguard genomic integrity by regulating DSB formation in various manners ensuring that when DNA replication or anaphase I do occur, they proceed without error. Consistent with the requirement to buffer natural variation—polymorphisms, temperature and nutritional status have all been reported to impact recombination frequencies [62], [63], [64], [65]. The observation that isogenic Spo11 hypomorphic S. cerevisiae strains produce wide ranges of recombination frequencies further illustrates the need for a foolproof system to buffer biological variability on a cell-to-cell basis even when an identical genetic complement is present [16]. The Mec1/Rad17/Rad24 systems, at least in S. cerevisiae, clearly ensure that prophase I duration strictly matches the specific situation of the cell at hand; suppressing premature anaphase I entry but also preventing prophase I from running longer than is required, ensuring succession into the protective sporulated state is as fast as possible. Simultaneously, Tel1, alongside Mec1, regulate DSB distributions in such a way to allow fruitful and appropriate levels of genetic exchange without risk to cellular survival. Ultimately, the complexity of the homeostatic mechanism considered here underscores the complex and multifaceted nature of the meiotic process. DSB homeostasis has likely arisen, out of necessity, to be both robust and efficient, and despite its heavy evolutionary demand upon the pre-existing cellular pathways, it has remained largely conserved—contributing critical regulation to the highly advantageous process of sexual reproduction.