Novel mechanistic insights into the role of Mer2 as the keystone of meiotic DNA break formation

Abstract

One of the defining features of sexual reproduction is the recombination events that take place during meiosis I. Recombination is both evolutionarily advantageous, but also mechanistically necessary to form the crossovers that link homologous chromosomes. Meiotic recombination is initiated through the placement of programmed double-strand DNA breaks (DSBs) mediated by the protein Spo11. The timing, number, and physical placement of DSBs are carefully controlled through a variety of protein machinery. Previous work has implicated Mer2(IHO1 in mammals) to be involved in both the placement of breaks, and their timing. In this study we use a combination of protein biochemistry and biophysics to extensively characterise various roles of the Mer2. We gain further insights into the details of Mer2 interaction with the PHD protein Spp1, reveal that Mer2 is a novel nucleosome binder, and suggest how Mer2’s interaction with the HORMA domain protein Hop1 (HORMAD1/2 in mammals) is controlled.

Chromosome Organization in Early Meiotic Prophase

“…Hop1 and Red1 play a role in DSB formation by serving as a platform for the Mer2/Mei4/Rec114 DSB proteins ( Panizza et al, 2011 ; Figure 2 ) that then promote Spo11 catalytic activity through direct or indirect interactions with Spo11 ( Yadav and Claeys Bouuaert, 2021 ). This Hop1/Red1 function is mediated by the direct interaction between Hop1 and Mer2 in S. cerevisiae ( Rousova et al, 2020 ), and between their orthologs Hop1 and Rec15 in S. pombe ( Kariyazono et al, 2019 ). In the absence of Rec8, Hop1/Red1 and Rec114 still colocalize, but their positioning is altered ( Panizza et al, 2011 ).…”

“…Thus, the potential DSB sites, which are promoter regions and have accessible chromatin, are brought, or stabilized to the axis thanks to the partly characterized interactions of H3K4me3 with Spp1 and of Spp1 with Mer2 ( Acquaviva et al, 2013 ; Sommermeyer et al, 2013 ; Adam et al, 2018 ). How the RMM complex is localized remains to be understood and the interaction detected between HORMAD1 and IHO1 ( Stanzione et al, 2016 ) and between Hop1 and Mer2 ( Rousova et al, 2020 ) is one determinant for this localization.…”

Mechanism and Control of Meiotic DNA Double-Strand Break Formation in S. cerevisiae

“…A recent study independently reported phase separation by Mer2 and its mouse homolog IHO1 ( Tsai et al, 2020 ). In addition, Mer2 was shown to bind directly to histone octamers, suggesting the possibility that the condensates may involve chromatinized templates, not only naked DNA ( Rousova et al, 2020 ).…”

A new phase in meiotic cell division

“…8). Chromosome-associated proteins of interest also include Spp1, which recognizes molecular modifications on histone proteins bound to hotspot DNA, and might recruit these sequences to RMM condensates for breakage [8][9][10] .…”