Telomere elongation chooses TERRA ALTernatives

Abstract

Alternative Lengthening of Telomeres (ALT) mechanisms allow telomerase-negative immortal cells to buffer replicative telomere shortening. ALT is naturally active in a number of human cancers and might be selected upon telomerase inactivation. ALT is thought to operate through homologous recombination (HR) occurring between telomeric repeats from independent chromosome ends. Indeed, suppression of a number of HR factors impairs ALT cell proliferation. Yet, how HR is initiated at ALT telomeres remains elusive. Mounting evidence suggests that the long noncoding telomeric RNA TERRA renders ALT telomeres recombinogenic by forming RNA:DNA hybrids with the telomeric C-rich strand. TERRA and telomeric hybrids act in concert with a number of other factors, including the RNA endoribonuclease RNaseH1 and the single stranded DNA binding protein RPA. The functional interaction network built upon these different players seems indispensable for ALT telomere maintenance, and digging into the molecular details of this previously unappreciated network might open the way to novel avenues for cancer treatments.

Keywords: ALT; RNA:DNA hybrids; RPA; TERRA; telomere elongation; telomere recombination; telomere transcription.

Figure 1.

Hypothetical model for TERRA-mediated telomere elongation in ALT cells. TERRA associates with ALT telomeres possibly through 2 independent mechanisms: formation of co-transcriptional and perhaps post-transcriptional RNA:DNA hybrids with the C-rich telomeric strand and physical interaction with TRF1 (in blue) and TRF2 (in green) within the shelterin multiprotein complex. Stripping off TERRA from telomeric hybrids would generate ss C-rich DNA that could be immediately bound by RPA. Although not indicated, RPA can also associate with G-rich ss DNA. In addition, TERRA molecules, which are elevated in ALT cells, would further prevent RPA dissociation from telomeres in G2/M. A switch between RPA and RAD51 could mediate homology searches and annealing between C-rich ss DNA previously engaged in a hybrid and the G-rich ss overhangs from heterologous telomeres. The C-rich strand of telomeric hybrid-containing telomeres could therefore serve as a template for de novo synthesis of telomeric repeats, which are directly added to the overhangs of the invading telomeres.