Nucleolar organization, ribosomal DNA array stability, and acrocentric chromosome integrity are linked to telomere...

Area of Science:

• Cell Biology
• Genetics
• Molecular Biology

Background:

• Acrocentric human chromosomes contain ribosomal RNA genes (rDNA) in nucleolar organizing regions crucial for nucleolus formation.
• Telomere dysfunction, induced by mutant TRF2 (dnTRF2), causes acrocentric fusions and nucleolar defects, but the underlying mechanisms are unclear.

Purpose of the Study:

• To investigate the mechanisms linking telomere dysfunction to acrocentric chromosome instability and nucleolar defects.
• To elucidate the role of TRF2 and rDNA in telomere-mediated chromosomal instability.

Main Methods:

• Utilized a controllable dnTRF2 system to induce and study telomere dysfunction.
• Employed RNAi knockdown of TRF2 to assess its role.
• Analyzed nucleolar and chromosomal changes, including rDNA decondensation and UBF coating.

Main Results:

• TRF2 normally associates with the nucleolus and rDNA.
• dnTRF2 or TRF2 knockdown leads to gross nucleolar and chromosomal changes.
• Nucleolar changes and rDNA decondensation precede DNA damage and morphological alterations at acrocentric short arms.
• UBF coating of decondensed rDNA physically links acrocentric chromosomes, promoting fusion.

Conclusions:

• Telomere dysfunction disrupts nucleolar stability and the structural integrity of acrocentric chromosomes, particularly rDNA arrays.
• Telomeric stress impacts chromosome structure beyond telomeres, affecting rDNA arrays and promoting acrocentric fusions.
• Findings are relevant to Robertsonian translocation formation and DNA damage-induced acrocentric fusions.