Structural Biochemistry of Meiotic Double Strand Break Control

• Applicant: Dr. John Weir
• Subject Area: Biochemistry ; Biophysics ; Structural Biology
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 445087119

• Final Report Year: 2025

Final Report Abstract

Meiotic recombination drives both the continuation and the remarkable diversity of life. During the formation of specialised cells called gametes (e.g., egg and sperm), an individual’s genome is halved. When two such gametes unite, they create a new organism with a unique genetic makeup. To ensure that only half the genetic material is transmitted—and to shuffle genes for variety—cells rely on a process called recombination. It begins with carefully orchestrated double-stranded DNA breaks (DSBs). Although DNA breaks normally pose a risk, meiosis uses them under strict control: at specific genome sites (spatial), within a set time window (temporal), and in limited number (numerical). These safeguards prevent permanent damage while still promoting valuable genetic rearrangements. Our research centers on the proteins that regulate these breaks, revealing how precise control is maintained. We used budding yeast as a genetically tractable model, then extended our findings to mammalian systems, which share similar meiotic mechanisms but add intriguing complexities. In a novel step, we also investigated meiotic proteins from brown algae—an often overlooked yet essential group for marine ecosystems and the global carbon cycle. By studying these proteins in vitro, we aim to deepen our understanding of how recombination operates across diverse branches of life.

Publications

• Novel mechanistic insights into the role of Mer2 as the keystone of meiotic DNA break formation. eLife, 10.
  Rousová, Dorota; Nivsarkar, Vaishnavi; Altmannova, Veronika; Raina, Vivek B.; Funk, Saskia K.; Liedtke, David; Janning, Petra; Müller, Franziska; Reichle, Heidi; Vader, Gerben & Weir, John R.
  
• Organizational principles governing assembly and activation of the meiosis-specific Red1-Hop1-Mek1 complex. openRxiv.
  Chen, Linda; Nivsarkar, Vaishnavi N.; Funk, Saskia K.; Weir, John R. & Vader, Gerben
  
• Exploring Meiosis in Brown Algae: Meiotic Axis Proteins in the model brown alga Ectocarpus. openRxiv.
  Kane, Emma I.; Trefs, Lioba S.; Eckert, Lena; Coelho, Susana M. & Weir, John R.
  
• Seeding the meiotic DNA break machinery and initiating recombination on chromosome axes. Nature Communications, 15(1).
  Dereli, Ihsan; Telychko, Vladyslav; Papanikos, Frantzeskos; Raveendran, Kavya; Xu, Jiaqi; Boekhout, Michiel; Stanzione, Marcello; Neuditschko, Benjamin; Imjeti, Naga Sailaja; Selezneva, Elizaveta; Tuncay, Hasibe; Demir, Sevgican; Giannattasio, Teresa; Gentzel, Marc; Bondarieva, Anastasiia; Stevense, Michelle; Barchi, Marco; Schnittger, Arp; Weir, John R. ... & Tóth, Attila
  
• The molecular machinery of meiotic recombination. Biochemical Society Transactions, 52(1), 379-393.
  Chen, Linda & Weir, John R.