New & Noteworthy

Role of Npl3p in regulating senescence rates

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.

From Perez-Martinez L et al., 2022

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

Tags: telomere, telomere length, senescence, Saccharomyces cerevisiae, Homology-Directed Repair

C-Circles, an ALT Plan for Telomere Restoration

February 18, 2022

The telomerase ribonucleoprotein complex is the primary means by which yeast cells maintain telomeres. However, it turns out that cells lacking functional telomerase have a backup plan to restore telomere length by “alternative lengthening of telomeres” (ALT). ALT employs recombination via extrachromosomal telomere elements called C-circles. In a process for which the reasons remain unclear, C-circles get paired with eroded telomeres at the nuclear pore complex on the nuclear membrane. This pairing requires the SAGA/TREX2 complex and, once paired, the recombination between C-circles and telomeres appears to be effected by Rad59p, the paralog of Rad52p.

Model of type II telomere recombination that relies on telomeric circles, from Aguilera et al.

This interesting model is described in a recent paper in The EMBO Journal, in which Aguilera et al. adapt a method developed in human cancer studies to detect ALT and C-circles in yeast. In humans, ~10% of cancers depend on ALT for unchecked growth. In yeast, cells with ALT were able to be detected as survivors among telomerase mutant (est2∆) cells.

As other types of extrachromosomal DNA circles were previously reported to associate with the nuclear pore complex, the authors addressed the possibility that C-circles bind the NPC and demonstrated it clearly. They also showed the circles interact with the SAGA/TREX2 complex, which favors telomere recombination.

The novel finding that ALT in yeast so closely mirrors that of some human cancer cells is a boon to study of these cancers. The ability to develop ALT inhibitors in yeast would provide a new set of potential anticancer therapies, making this an ideal model system.

Categories: Research Spotlight

Tags: cell aging, cancer, yeast model for human disease, senescence, telomeres, Saccharomyces cerevisiae