Functions and Regulation of Meiotic HORMA-Domain Proteins

Abstract

During meiosis, homologous chromosomes must recognize, pair, and recombine with one another to ensure the formation of inter-homologue crossover events, which, together with sister chromatid cohesion, promote correct chromosome orientation on the first meiotic spindle. Crossover formation requires the assembly of axial elements, proteinaceous structures that assemble along the length of each chromosome during early meiosis, as well as checkpoint mechanisms that control meiotic progression by monitoring pairing and recombination intermediates. A conserved family of proteins defined by the presence of a HORMA (HOp1, Rev7, MAd2) domain, referred to as HORMADs, associate with axial elements to control key events of meiotic prophase. The highly conserved HORMA domain comprises a flexible safety belt sequence, enabling it to adopt at least two of the following protein conformations: one closed, where the safety belt encircles a small peptide motif present within an interacting protein, causing its topological entrapment, and the other open, where the safety belt is reorganized and no interactor is trapped. Although functional studies in multiple organisms have revealed that HORMADs are crucial regulators of meiosis, the mechanisms by which HORMADs implement key meiotic events remain poorly understood. In this review, we summarize protein complexes formed by HORMADs, discuss their roles during meiosis in different organisms, draw comparisons to better characterize non-meiotic HORMADs (MAD2 and REV7), and highlight possible areas for future research.

Building the synaptonemal complex: Molecular interactions between the axis and the central region

“…We have limited our discussion of the many meiotic functions of the SC and of molecular interactions within the axis and within the CR. These topics have been covered in recent excellent reviews [3][4][5][6][7][8][9][10][11].…”

Chromatin binding by HORMAD proteins regulates meiotic recombination initiation

“…Axis proteins organize each replicated chromosome into a linear array of chromatin loops and help activate, distribute, and resolve meiotic recombination events (Ito and Shinohara, 2022 ; Ur and Corbett, 2021 ; Zickler and Kleckner, 2015 ). The axis comprises three main components: (1) cohesin complexes with one or more meiosis-specific subunits (Sakuno and Hiraoka, 2022 ); (2) filamentous axis core proteins (West et al, 2019 ); and (3) meiotic HORMA domain (HORMAD) proteins (Rosenberg and Corbett, 2015 ; Prince and Martinez-Perez, 2022 ). Cohesins are ring-like complexes that bind DNA and processively extrude chromatin loops to organize chromosomes throughout the cell cycle (Yatskevich et al, 2019 ).…”

“…The function of HORMAD proteins in the activation and later repair of meiotic recombination is well conserved across eukaryotes but is best understood in the budding yeast Saccharomyces cerevisiae (Prince and Martinez-Perez, 2022 ). In S. cerevisiae , the HORMAD ortholog Hop1 contributes to axial element integrity (Klein et al, 1999 ; Hollingsworth et al, 1990 ) and acts in the very early stages of meiotic recombination by mediating the recruitment of the DSB-forming endonuclease Spo11 and its accessory proteins (Panizza et al, 2011 ; Woltering et al, 2000 ).…”

Exportin-mediated nucleocytoplasmic transport maintains Pch2 homeostasis during meiosis

“…The meiotic roles of Pch2 are exerted through its action on its preferred client: the HORMAD protein Hop1 [ 39 , 40 ]. As a member of the HORMAD family, Hop1 contains a flexible safety belt in its HORMA domain, which enables it to adopt an open/unbuckled or closed conformation [ 41 , 42 ].…”