May 06, 2022
Telomeres, regions of repetitive DNA at the terminal ends of linear chromosomes, function as protective caps essential to maintain chromosomal structural integrity. Telomeres shorten with every cell cycle and eventually activate replicative senescence (a checkpoint-mediated cell cycle arrest) once they reach a critical length. Regulation of telomere length is essential as an uncontrolled shortening of telomeres can cause organismal aging, and the inability to trigger senescence can result in tumor development. In budding yeast, regulatory factors such as TERRA (telomere repeat containing RNA), a RNAPII-transcribed long non-coding RNA at all telomeres, and R-loops promote Homology-Directed Repair (HDR) at critically short telomeres. Whereas at long telomeres, RNase H2 and Rat1p are recruited and function to degrade TERRA and R loops during S phase.
An interesting new study by Perez-Martinez L et al. in EMBO identifies a telomere-binding protein, Npl3p, to stabilize R-loops at critically short telomeres to prevent premature senescence. The authors propose that at short telomeres, TERRA recruits Npl3p, and the bound protein stabilizes R-loops by limiting access to degrading enzymes like Rat1p and RNAse H2. As a result, the stabilized R-loops promote HDR, and telomeres are elongated to prevent early senescence. Conversely, the absence of Npl3p causes R-loop instability and a defective HDR mechanism, unable to constrain the senescence rates.
The authors additionally show that like TERRA and R-loops, Npl3p levels are regulated in a cell-cycle-dependent manner, with increased accumulation during the early S phase followed by a decline in the late S phase. The study also points to the fact that several proteins or complexes, including Npl3p and Tlc1p, accumulate strongly at short telomeres and in the presence of RNAse A and RNAse H, this interaction is lost.
The study highlights Npl3p as an essential factor in studying the diseases associated with dysregulation of telomere length and senescence rates.
Categories: Research Spotlight