REXO5 promotes genomic integrity through regulating R-loop using its exonuclease activity

Area of Science:

• Molecular Biology
• Cancer Research
• Genetics

Background:

• Chronic myeloid leukemia (CML) pathogenesis involves altered gene expression, but underlying mechanisms remain unclear.
• The BCR::ABL1 fusion gene drives CML progression by modulating gene expression.

Purpose of the Study:

• To identify novel genes involved in CML pathogenesis.
• To elucidate the molecular mechanisms of REXO5 in DNA damage response and CML.

Main Methods:

• Utilized REXO5 knockout (KO) K562 cell lines and wild-type (WT) cells.
• Investigated REXO5 translocation to DNA damage sites via its RNA recognition motif (RRM).
• Assessed R-loop accumulation, DNA damage, and ATR-CHK1 activation in REXO5 KO cells.

Main Results:

• REXO5 mRNA expression is elevated in CML patients.
• REXO5 KO cells exhibit increased R-loops and DNA damage compared to WT cells.
• REXO5 translocates to DNA damage sites, binds R-loops, and degrades mRNA via its exonuclease domain, regulating R-loop levels and ATR-CHK1 activation.

Conclusions:

• REXO5 plays a critical role in the physiological control of R-loops through its exonuclease activity.
• REXO5's function in R-loop regulation provides novel insights into CML pathogenesis.
• Dysregulation of REXO5 may contribute to CML development and progression.