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

Area of Science:

• Genetics
• Molecular Biology
• Cancer Research

Background:

• APOBEC3 cytidine deaminases, particularly APOBEC3A, are implicated in cancer mutagenesis and DNA damage.
• Mechanisms maintaining genome stability against APOBEC3A activity remain largely unknown.

Purpose of the Study:

• To identify cellular factors essential for genome stability in the presence of active APOBEC3A.
• To investigate the role of the Structural Maintenance of Chromosomes 5/6 (SMC5/6) complex in response to APOBEC3A-induced DNA damage.

Main Methods:

• Unbiased genome-wide screening to identify essential genes for cell viability with active APOBEC3A.
• Analysis of APOBEC3A mutagenesis patterns in human tumors with varying SMC5/6 function.
• Assessment of DNA replication dynamics and DNA breaks in cells with and without SMC5/6 function under APOBEC3A activity.

Main Results:

• The SMC5/6 complex was identified as 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 damage and re-initiation.
• Loss of SMC5/6 function exacerbates DNA breaks and abrogates replication tract lengthening upon APOBEC3A activity.

Conclusions:

• Replication fork lengthening is a DNA damage response to APOBEC3A activity that promotes genome stability via SMC5/6.
• SMC5/6 is critical for managing APOBEC3A-induced DNA damage and maintaining genome integrity.
• SMC5/6 represents a potential therapeutic vulnerability in cancers exhibiting high APOBEC3A activity.