New Solutions to Old Problems: Molecular Mechanisms of Meiotic Crossover Control

Abstract

During scientific investigations, the explanation of remarkably interesting phenomena must often await development of new methods or accrual of new observations that in retrospect can lead to lucid answers to the initial problem. A case in point is the control of genetic recombination during meiosis, which leads to crossovers between chromosomes critical for production of healthy offspring. Crossovers must be properly placed along meiotic chromosomes for their accurate segregation. Here, we review observations on two aspects of meiotic crossover control - crossover interference and repression of crossovers near centromeres, both observed more than 85 years ago. Only recently have relatively simple molecular mechanisms for these phenomena become clear through advances in both methods and understanding the molecular basis of meiotic recombination.

Keywords: DNA break hotspot clusters; centromeric repression; crossover interference; heterochromatin; linear element proteins; sister chromatid cohesins.

Figure 1.. Chromosomal segregation during meiosis.

After replication, sister chromatids of each parent are held together by cohesin complexes deposited at points across the chromosomal arms (purple rings) and especially densely at the pericentric regions (green rings). One or more crossovers between homologs in the chromosomal arms and sister chromatid cohesion are required in most species for proper reductional division at meiosis I (MI) (second panel from the left), but a crossover too near another may leave too little cohesion to be effective (third panel from the left). A crossover near the telomere (not shown) also leaves too little cohesion distal to the crossover to be effective [11]. In the absence of crossovers, there is no tension generated between homologs, which results in missegregation and aneuploidy (left-most panel). Pericentric crossovers may lead to misorientation of the kinetochores or loss of sister chromatid cohesion at the centromeres, which also results in missegregation and aneuploidy (right-most panel). Each solid line depicts double-stranded DNA of a chromatid; red and blue indicate a representative homolog pair (one chromosome from each parent); central circles indicate the centromeres; dashed lines depict microtubules that pull the chromosomes toward the spindle pole bodies (yellow stars) at the opposite poles.

Figure 2.. Clustering model for crossover interference [22].

DSB hotspots (green circles) on each pair of sister chromatids (one homolog; panel A) or on both homologs (panel B) are gathered into a cluster in a limited region (bounded by dotted grey lines). Within each cluster, one DSB (yellow lightning bolt) is formed and activates the Tel1 DNA damage protein kinase, which phosphorylates and inactivates some component of the DSB-forming complex (not shown). Consequently, at most only one crossover (CO) is made in each limited region. DSBs, and thus crossovers, are made independently on each homolog in panel A; two crossovers can occur close together more frequently than in panel B, and interference is stronger in species represented by panel B than in those represented by panel A.

Figure 3.. Mechanism for pericentric repression in S. pombe [47].

In euchromatic DNA, the major form in chromosomal arms, the meiosis-specific cohesin complex contains Rec8 and Rec11 subunits along with Smc1-Smc3. Rec11 recruits the linear element protein Rec10, which activates Spo11(Rec12)-dependent DSB formation. Other linear element proteins Rec25, Rec27, and Mug20 are recruited along with Rec10 at DSB hotspots. However, in heterochromatic DNA, the major form in pericentric regions, the cohesin complex contains Psc3 instead of Rec11; Psc3 does not bind Rec10 or activate DSB formation. Rec8-Psc3 specific loading is mediated by Swi6, an HP1 homolog, which specifically binds to H3 K9 methylated histones present in heterochromatin. This model is for S. pombe but is likely conserved even in mammals (see text). Each solid line indicates the double-stranded DNA of a chromatid.