The SMC5/6 complex prevents genotoxicity upon APOBEC3A-mediated replication stress

Area of Science:

• Genetics
• Molecular Biology
• Cancer Research

Background:

• APOBEC3 cytidine deaminases contribute to mutations in human cancers.
• APOBEC3A is a potent genotoxin causing DNA damage, but its impact on genome stability mechanisms remains unclear.

Approach:

• Utilized an unbiased genome-wide screen to identify factors crucial for cell survival during APOBEC3A activity.
• Investigated the role of the Structural Maintenance of Chromosomes 5/6 (SMC5/6) complex in maintaining genome integrity.
• Examined APOBEC3A-induced DNA damage, replication stress, and repair pathways in cells with varying SMC5/6 function.

Key Points:

• The SMC5/6 complex is essential for cell viability when APOBEC3A is active.
• APOBEC3A mutagenesis is absent in human tumors with SMC5/6 dysfunction, suggesting synthetic lethality.
• APOBEC3A activity causes replication tract lengthening, dependent on PrimPol, indicating DNA synthesis re-initiation.
• Loss of SMC5/6 function exacerbates DNA breaks and abrogates replication tract lengthening in response to APOBEC3A.

Conclusions:

• Replication fork lengthening is a DNA damage response to APOBEC3A activity that promotes genome stability via SMC5/6.
• SMC5/6 complex dysfunction represents a potential therapeutic vulnerability in cancers with active APOBEC3A.