Pathogenic variants in MAEA disrupt DNA replication fork stability and are associated with developmental...

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.