Mouse Slfn8 and Slfn9 genes complement human cells lacking SLFN11 during the replication stress response

Area of Science:

• Genetics
• Molecular Biology
• Cancer Research

Background:

• The Schlafen (SLFN)11 gene plays roles in HIV suppression, DNA damage response, and chemotherapy sensitivity.
• The evolutionary relationship between human SLFN11 and its mouse counterparts is not well-defined due to rapid gene family diversification.

Purpose of the Study:

• To investigate the functional conservation and potential orthology between human SLFN11 and mouse SLFN genes.
• To explore the role of mouse Slfn8 and Slfn9 in DNA damage response and cellular processes.

Main Methods:

• Utilizing microlaser-induced DNA damage to track protein recruitment.
• Complementation assays using human SLFN11-deficient cells.
• Assessing cell growth rates and sensitivity to DNA-damaging agents.
• Analyzing DNA repair foci, including RPA and RAD51, after DNA damage.

Main Results:

• Mouse SLFN8/9 and human SLFN11 were rapidly recruited to DNA damage sites.
• Expression of mouse Slfn8/9 rescued SLFN11 deficiency in human cells, restoring growth rates and drug sensitivity.
• Both mouse and human SLFN proteins accelerated stalled fork degradation and reduced RPA/RAD51 foci.

Conclusions:

• Mouse Slfn8 and Slfn9 genes likely possess orthologous functions to human SLFN11.
• This functional similarity supports the use of mouse models for studying SLFN11's biological roles.
• Findings facilitate in vivo research into SLFN11's mechanisms in cancer and viral infections.