ILF3 safeguards telomeres from aberrant homologous recombination as a telomeric R-loop reader

Area of Science:

• Molecular Biology
• Genetics
• Cancer Research

Background:

• Telomeres protect chromosome ends, but telomeric repeat-containing RNA (TERRA) can form R-loops.
• Dysregulated R-loops at telomeres are linked to cancer and genome instability.
• Mechanisms for R-loop recognition and regulation at telomeres remain unclear.

Purpose of the Study:

• To investigate the role of ILF3 in recognizing and regulating telomeric R-loops.
• To understand how ILF3 maintains telomere stability and homeostasis.
• To identify proteins interacting with ILF3 at telomeres.

Main Methods:

• Selective association of ILF3 with telomeric R-loops was investigated.
• ILF3 knockout models were used to assess telomere integrity.
• Proximity-dependent biotin identification (BioID) mapped the ILF3 interactome.
• Interaction between ILF3 and DHX9 was analyzed.

Main Results:

• ILF3 selectively binds to telomeric R-loops, preventing abnormal homologous recombination.
• ILF3 knockout causes excessive telomeric R-loops and DNA damage responses.
• ILF3 deficiency disrupts telomere homeostasis and the alternative lengthening of telomeres (ALT) pathway.
• ILF3 interacts with DNA/RNA helicases, including DHX9, potentially aiding R-loop resolution.

Conclusions:

• ILF3 acts as a reader of telomeric R-loops.
• ILF3 safeguards telomeres by preventing abnormal homologous recombination.
• ILF3 is crucial for maintaining telomere homeostasis and regulating the ALT pathway.