A pro-metastatic tRNA fragment drives Nucleolin oligomerization and stabilization of its bound metabolic mRNAs

Area of Science:

• Molecular Biology
• Cancer Research
• RNA Biology

Background:

• Stress induces tRNA cleavage into tRNA-derived fragments (tRFs), but their roles in disease are unclear.
• The function and regulation of tRFs in cancer progression remain poorly understood.

Purpose of the Study:

• To investigate the role of tRFs in breast cancer metastasis.
• To elucidate the molecular mechanisms by which tRFs contribute to cancer progression.

Main Methods:

• Small RNA sequencing to identify differentially expressed tRFs in breast cancer.
• Functional assays to determine the role of 5 RF^Cys in metastasis and cell survival.
• RNA-binding protein immunoprecipitation and transcriptomic analysis to identify binding partners and downstream targets.

Main Results:

• Increased abundance of 5 RF^Cys was observed during breast cancer metastatic progression.
• 5 RF^Cys is essential for lung colonization and cancer cell survival.
• Nucleolin was identified as a direct binding partner of 5 RF^Cys, promoting its oligomerization and the formation of a ribonucleoprotein complex.
• This complex protects metabolic transcripts (Mthfd1l, Pafah1b1) from degradation, impacting folate, one-carbon, and phosphatidylcholine metabolism.

Conclusions:

• A specific tRNA fragment (5 RF^Cys) actively promotes breast cancer metastasis.
• 5 RF^Cys functions by stabilizing key metabolic transcripts through interaction with Nucleolin.
• This mechanism highlights a novel pathway through which RNA fragments influence cancer progression and metabolism.