TERRA R-loops connect and protect sister telomeres in mitosis.

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• Sister telomere cohesion resolution is crucial for mitosis and depends on TRF1-tankyrase recruitment.
• In aged human cells, shortened telomeres exhibit insufficient TRF1/tankyrase recruitment, leading to persistent sister telomere cohesion.
• The precise mechanism maintaining this persistent cohesion in aging cells remains unclear.

Purpose of the Study:

• To elucidate the mechanism by which sister telomeres remain cohered in aged human cells.
• To investigate the role of telomere repeat-containing RNA (TERRA) and associated proteins in telomere cohesion.
• To understand how this process influences cellular senescence.

Main Methods:

• Investigated the role of RNA-binding protein C19orf43 in TERRA R-loop regulation at telomeres.
• Utilized RNaseH1 treatment to confirm the role of RNA-DNA hybrids in sister telomere cohesion.
• Assessed DNA damage and replicative senescence in cells with altered C19orf43 levels.

Main Results:

• TERRA forms RNA-DNA hybrids (R-loops) that physically hold sister telomeres together.
• The tankyrase-interacting protein C19orf43 is essential for repressing TERRA R-loops.
• Depletion of C19orf43 in aged cells leads to persistent telomere cohesion, which is reversed by RNaseH1.
• C19orf43 depletion in aged cells reduces DNA damage and delays senescence.

Conclusions:

• TERRA-mediated R-loops are the key mechanism maintaining persistent sister telomere cohesion in aged cells.
• C19orf43 acts as a repressor of these cohesion-promoting R-loops.
• The inability of shortened telomeres to recruit R-loop-repressing machinery facilitates a controlled onset of senescence.