Abstract
Correct segregation of meiotic chromosomes depends on DNA crossovers (COs) between homologs that culminate into visible physical linkages called chiasmata. COs emerge from a larger population of joint molecules (JM), the remainder of which are repaired as noncrossovers (NCOs) to restore genomic integrity. We present evidence that the RNF212-like C. elegans protein ZHP-4 cooperates with its paralog ZHP-3 to enforce crossover formation at distinct steps during meiotic prophase: in the formation of early JMs and in transition of late CO intermediates into chiasmata. ZHP-3/4 localize to the synaptonemal complex (SC) co-dependently followed by their restriction to sites of designated COs. RING domain mutants revealed a critical function for ZHP-4 in localization of both proteins to the SC and for CO formation. While recombination initiates in zhp-4 mutants, they fail to appropriately acquire pro-crossover factors at abundant early JMs, indicating a function for ZHP-4 in an early step of the CO/NCO decision. At late pachytene stages, hypomorphic mutants exhibit significant levels of crossing over that are accompanied by defects in localization of pro-crossover RMH-1, MSH-5 and COSA-1 to designated crossover sites, and by the appearance of bivalents defective in chromosome remodelling required for segregation. These results reveal a ZHP-4 function at designated CO sites where it is required to stabilize pro-crossover factors at the late crossover intermediate, which in turn are required for the transition to a chiasma that is required for bivalent remodelling. Our study reveals an essential requirement for ZHP-4 in negotiating both the formation of COs and their ability to transition to structures capable of directing accurate chromosome segregation. We propose that ZHP-4 acts in concert with ZHP-3 to propel interhomolog JMs along the crossover pathway by stabilizing pro-CO factors that associate with early and late intermediates, thereby protecting designated crossovers as they transition into the chiasmata required for disjunction.
Highlights
During the two specialized divisions of meiosis, a single round of DNA replication is followed by two rounds of segregation that produce gametes with half the parental number of chromosomes
We investigate here the role of ZHP-4, and its partner ZHP-3 which form a complex that associates along paired chromosomes and with crossover sites
ZHP-3/4 are conserved proteins found in many organisms that function in recruiting proteins required to decide which DNA event will become a crossover and how this DNA event is coordinated with changes in chromosome structure
Summary
During the two specialized divisions of meiosis, a single round of DNA replication is followed by two rounds of segregation that produce gametes with half the parental number of chromosomes. An early step in this process is resection of a DSB end to form a single-stranded stretch of DNA that can recruit Rad, an event that initiates invasion of the homologous chromosome and the formation of a joint molecule (JM) intermediate to link the homologs (reviewed in [1]) Resolution of these JMs can proceed through a crossover (CO) or noncrossover (NCO) pathway and the route chosen at any given site is carefully monitored. A decision must be made to stabilize certain JM intermediates for entry into the CO pathway, while the remaining events are repaired as NCOs [5] These events are tightly regulated in Caenorhabditis elegans, where an estimated 5–12 DSBs along a chromosome pair must be processed to yield a single exchange event [6,7,8] that serves to both physically link the homologous chromosomes and asymmetrically reconfigure the bivalent in preparation for interaction with the segregation machinery (reviewed in [9]). The pattern of ZHP-3/4 localization is reminiscent of other pro-crossover factors (RMH-1, MSH-5, and COSA-1), which begin with abundant early localization that is confined to the sites of the obligate crossovers at late pachytene stages, and disappears as chromosomes desynapse and chiasmata emerge [11,12]
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