Peroxiredoxin 1 safeguards the nucleolar genome from oxidative damage

Area of Science:

• Molecular Biology
• Genetics
• Cell Biology

Background:

• Peroxiredoxin 1 (PRDX1) is a crucial antioxidant enzyme involved in redox signaling.
• PRDX1-null mice display genomic instability and accelerated tumorigenesis, but the underlying mechanisms are unclear.
• Understanding PRDX1's role is vital for comprehending genomic stability and cancer development.

Purpose of the Study:

• To elucidate the molecular mechanisms by which PRDX1 deficiency leads to genomic instability.
• To investigate the impact of PRDX1 loss on nucleolar function and ribosome biogenesis.
• To identify the specific DNA damage response pathways activated by PRDX1 deficiency in the nucleolus.

Main Methods:

• Analysis of PRDX1-null mouse models.
• Assessment of nucleolar morphology and RNA Polymerase I (POL-I) dependent transcription.
• Evaluation of secondary DNA structure stability (RNA-DNA hybrids, G-quadruplex DNA).
• Investigation of rRNA levels and processing.
• Detection of DNA damage response activation (ATM, TCOF1, MRN complex).

Main Results:

• PRDX1 deficiency alters nucleolar morphology and impairs POL-I dependent transcription of pre-ribosomal RNAs.
• Oxidative stress-induced nucleolar dysfunction promotes secondary DNA structure stability, leading to genomic instability.
• PRDX1 loss reduces nascent rRNA levels and impairs rRNA processing, affecting ribosome biogenesis.
• PRDX1 deficiency triggers nucleolar DNA damage response, including ATM activation and NBS1 recruitment to rDNA loci.
• NBS1 accumulation correlates with repressed rDNA transcription, potentially safeguarding the nucleolar genome.

Conclusions:

• PRDX1 is essential for maintaining nucleolar integrity and ribosome biogenesis.
• Redox-dependent regulation of rDNA transcription and processing by PRDX1 is critical for genomic stability.
• PRDX1 deficiency activates a nucleolar DNA damage response, highlighting its role in preventing oxidative stress-induced genomic damage.