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Updated: Sep 9, 2025
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
Pathogenic variants in MAEA disrupt DNA replication fork stability and are associated with developmental
Elham Zeinali1, Fatemeh Mashayekhi1, Rabih Abou Farraj2
1Department of Oncology, Faculty of Medicine & Dentistry, University of Alberta, 11560 University Avenue, Edmonton T6G 1Z2, Alberta, Canada.
Abstract:
Replication stress (RS) poses a threat to genome stability and drives genomic rearrangements. The homologous recombination (HR) pathway repairs stalled replication forks (RFs) and prevents such instability. Through an E3 ubiquitin ligase screen aimed at identifying regulators of RAD51, we identified macrophage erythroblast attacher (MAEA), a core component of C-terminal to Lish (CTLH) E3 ubiquitin ligase complex, as a regulator of the HR pathway. Loss of MAEA impairs RAD51 recruitment at stalled RFs, leading to increased sensitivity to RS-inducing agents and excessive degradation of nascent DNA strands. Mechanistically, MAEA associates with and mediates the ubiquitylation of Ku80, enabling its removal from RF ends and facilitating the loading of RAD51. Notably, MAEA deficiency is associated with a developmental disorder involving microcephaly, craniofacial abnormalities, ocular defects, and heart malformations. Functional assays show that disease-linked MAEA variants (R34C, E349G, Y394D, and M396R) are defective in RS response. These findings establish MAEA as an essential factor in RF protection and genome integrity.
Insights
Macrophage erythroblast attacher (MAEA) is crucial for repairing DNA replication stress by aiding RAD51 loading. Loss of MAEA compromises genome stability and is linked to developmental disorders.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- Replication stress (RS) threatens genome stability, potentially causing genomic rearrangements.
- The homologous recombination (HR) pathway is vital for repairing stalled replication forks (RFs) and maintaining genomic integrity.
Purpose of the Study:
- To identify novel regulators of the HR pathway involved in RAD51 function.
- To elucidate the role of macrophage erythroblast attacher (MAEA) in genome stability and replication fork protection.
Main Methods:
- Conducted an E3 ubiquitin ligase screen to identify RAD51 regulators.
- Performed functional assays to assess the impact of MAEA loss and variants on RS response.
- Investigated the mechanism of MAEA action, including its association with and ubiquitylation of Ku80.
Main Results:
- Identified MAEA, a component of the C-terminal to Lish (CTLH) E3 ubiquitin ligase complex, as a regulator of HR.
- MAEA deficiency impairs RAD51 recruitment to stalled RFs, increases sensitivity to RS-inducing agents, and leads to nascent DNA strand degradation.
- MAEA mediates Ku80 ubiquitylation, facilitating its removal from RF ends and promoting RAD51 loading.
- Disease-associated MAEA variants exhibit defects in RS response.
Conclusions:
- MAEA is essential for protecting replication forks and maintaining genome integrity.
- MAEA's role in HR and RF protection is critical, and its dysfunction underlies specific developmental disorders.
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