The FANCC–FANCE–FANCF complex is evolutionarily conserved and regulates meiotic recombination

• Published in: Nucleic acids research Vol. 51; no. 6; pp. 2516 - 2528
• Main Authors: Singh, Dipesh Kumar, Gamboa, Rigel Salinas, Singh, Avinash Kumar, Walkemeier, Birgit, Van Leene, Jelle, De Jaeger, Geert, Siddiqi, Imran, Guerois, Raphael, Crismani, Wayne, Mercier, Raphael
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 11-04-2023
• Subjects: Arabidopsis - genetics; Arabidopsis - metabolism; DNA - metabolism; Fanconi Anemia Complementation Group C Protein - genetics; Fanconi Anemia Complementation Group C Protein - metabolism; Fanconi Anemia Complementation Group F Protein - genetics; Fanconi Anemia Complementation Group F Protein - metabolism; Fanconi Anemia Complementation Group Proteins - genetics; Fanconi Anemia Complementation Group Proteins - metabolism; Homologous Recombination; Humans; Meiosis; NAR Breakthrough
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkac1244

Abstract
At meiosis, programmed meiotic DNA double-strand breaks are repaired via homologous recombination, resulting in crossovers (COs). From a large excess of DNA double-strand breaks that are formed, only a small proportion gets converted into COs because of active mechanisms that restrict CO formation. The Fanconi anemia (FA) complex proteins AtFANCM, MHF1 and MHF2 were previously identified in a genetic screen as anti-CO factors that function during meiosis in Arabidopsis thaliana. Here, pursuing the same screen, we identify FANCC as a new anti-CO gene. FANCC was previously only identified in mammals because of low primary sequence conservation. We show that FANCC, and its physical interaction with FANCE–FANCF, is conserved from vertebrates to plants. Further, we show that FANCC, together with its subcomplex partners FANCE and FANCF, regulates meiotic recombination. Mutations of any of these three genes partially rescues CO-defective mutants, which is particularly marked in female meiosis. Functional loss of FANCC, FANCE, or FANCF results in synthetic meiotic catastrophe with the pro-CO factor MUS81. This work reveals that FANCC is conserved outside mammals and has an anti-CO role during meiosis together with FANCE and FANCF.
Lay Summary
The Fanconi Anemia (FA) pathway is the subject of intense interest owing to the role of FA as a tumor suppressor. Three FA complex proteins, FANCM, MHF1 and MHF2, were identified as factors that suppress crossover during meiosis in the model plant Arabidopsis thaliana. Here, the authors extended these findings and identified a novel anti-crossover factor and showed that it encodes the plant FANCC homolog, which was previously thought to be vertebrate-specific. They further showed that FANCC regulates meiotic crossover together with two other FA proteins, FANCE and FANCF. This suggests that the FANCC–E–F subcomplex was already regulating DNA repair in the common ancestor of all living eukaryotes.
Graphical Abstract
Graphical Abstract
The FANCC-FANCE–FANCF complex is conserved from humans to plants, with a similar predicted structure. The complex regulates meiotic recombination and limits crossovers. Created with Biorender.com.