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

Dylan F Fingerman1,2, David R O'Leary1,2, Ava R Hansen1,2,3

  • 1Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.

The EMBO Journal
|June 17, 2024
PubMed

Insights

The Structural Maintenance of Chromosomes 5/6 (SMC5/6) complex is crucial for cell survival when APOBEC3A causes DNA damage. SMC5/6 dysfunction prevents APOBEC3A mutagenesis, revealing a potential cancer therapy target.

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.
Keywords:
Cancer MutagenesisCytidine DeaminaseGenome IntegrityMutational SignaturesReplication Stress

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