RAD51 and RTEL1 compensate telomere loss in the absence of telomerase

Abstract

Replicative erosion of telomeres is naturally compensated by telomerase and studies in yeast and vertebrates show that homologous recombination can compensate for the absence of telomerase. We show that RAD51 protein, which catalyzes the key strand-invasion step of homologous recombination, is localized at Arabidopsis telomeres in absence of telomerase. Blocking the strand-transfer activity of the RAD51 in telomerase mutant plants results in a strikingly earlier onset of developmental defects, accompanied by increased numbers of end-to-end chromosome fusions. Imposing replication stress through knockout of RNaseH2 increases numbers of chromosome fusions and reduces the survival of these plants deficient for telomerase and homologous recombination. This finding suggests that RAD51-dependent homologous recombination acts as an essential backup to the telomerase for compensation of replicative telomere loss to ensure genome stability. Furthermore, we show that this positive role of RAD51 in telomere stability is dependent on the RTEL1 helicase. We propose that a RAD51 dependent break-induced replication process is activated in cells lacking telomerase activity, with RTEL1 responsible for D-loop dissolution after telomere replication.

Roles of RAD51 and RTEL1 in telomere and rDNA stability in Physcomitrella patens

“…The results of both assays demonstrated that neither telomerase expression, nor the activity changes significantly in either of the mutants. These results are consistent with the recently described role of both genes in ALT in A. thaliana (Olivier et al ., ) and indicate that the critical telomere shortening observed in pprtel1 moss lines results from telomere rapid deletion events, rather than from an impaired telomerase function in these mutants.…”

“…The results of telomere analyses in pprad51‐1‐2 are consistent with the previous results obtained in corresponding mutants of A. thaliana and with the notion that in the presence of telomerase, RAD51 is not involved in telomere maintenance (Olivier et al ., ). In fact, this also corresponds to the general view of telomeres as recombination‐silent chromosome loci.…”

“…This situation is exemplified by the KU70/80 heterodimer, which acts in one of the main DSB repair pathways, non‐homologous end‐joining (NHEJ) (Boulton and Jackson, ), as well as in protection of blunt‐ended plant telomeres (Valuchova et al ., ), and which is an interaction factor of telomerase (Chai et al ., ; Ting et al ., ). Similarly, the RAD51 protein, the essential factor of another major DSB repair pathway – homologous recombination (HR) – acts also in an alternative telomere lengthening (ALT) in the absence of telomerase (Le et al ., ; Olivier et al ., ). Telomerase, a ribonucleoprotein complex, elongates telomeres, thereby compensating for their erosion due to incomplete replication by the lagging strand synthesis in each replication.…”

“…This observation indicated the role of RTEL1 in ALT, which otherwise partially compensates for the TERT loss (Ruckova et al ., ). The requirement for RTEL1 in multiple pathways to preserve genome stability in A. thaliana can be explained by its putative role in the destabilization of DNA loop structures, such as D‐loops and T‐loops (see above), and it has been demonstrated that RAD51‐dependent HR participates in ALT in A. thaliana (Olivier et al ., ). The authors also showed that this RAD51 role is dependent on RTEL1 helicase, possibly functioning in a dissolution of a displacement loop (D‐loop) during telomere replication.…”

Genetic analysis of the relation of telomere length‐related gene (RTEL1) and coronary heart disease risk

“…Cai et al (2017b) reported the associations between single nucleotide polymorphisms in the RTEL1 gene and stroke risk, and the result showed that the rs6010620, rs6010621, and rs6089953 were associated with an increased risk of stroke. However, Olivier, Charbonnel, Amiard, White, and Gallego () showed RAD51 and RTEL1 gene could compensate telomere loss and protect cell stability when telomere was absent. And another study indicated that the presence of rs6010620 and rs2297440 resulted in a decreased risk of astrocytoma (Jin et al, ).…”