Hyper telomere recombination accelerates replicative senescence and may promote premature aging

Abstract

Werner syndrome and Bloom syndrome result from defects in the RecQ helicases Werner (WRN) and Bloom (BLM), respectively, and display premature aging phenotypes. Similarly, XFE progeroid syndrome results from defects in the ERCC1-XPF DNA repair endonuclease. To gain insight into the origin of cellular senescence and human aging, we analyzed the dependence of sister chromatid exchange (SCE) frequencies on location [i.e., genomic (G-SCE) vs. telomeric (T-SCE) DNA] in primary human fibroblasts deficient in WRN, BLM, or ERCC1-XPF. Consistent with our other studies, we found evidence of elevated T-SCE in telomerase-negative but not telomerase-positive backgrounds. In telomerase-negative WRN-deficient cells, T-SCE—but not G-SCE—frequencies were significantly increased compared with controls. In contrast, SCE frequencies were significantly elevated in BLM-deficient cells irrespective of genome location. In ERCC1-XPF-deficient cells, neither T- nor G-SCE frequencies differed from controls. A theoretical model was developed that allowed an in silico investigation into the cellular consequences of increased T-SCE frequency. The model predicts that in cells with increased T-SCE, the onset of replicative senescence is dramatically accelerated even though the average rate of telomere loss has not changed. Premature cellular senescence may act as a powerful tumor-suppressor mechanism in telomerase-deficient cells with mutations that cause T-SCE levels to rise. Furthermore, T-SCE-driven premature cellular senescence may be a factor contributing to accelerated aging in Werner and Bloom syndromes, but not XFE progeroid syndrome.

RECQL4, the Protein Mutated in Rothmund-Thomson Syndrome, Functions in Telomere Maintenance

“…BLM may be important in the progression of the replication fork globally, whereas WRN may play a more specific role in telomere replication. Supporting this concept, Bailey and colleagues (62) recently demonstrated that depletion of WRN induces T-SCE, whereas depletion of BLM induces SCE at non-telomeric chromosome regions (i.e. global SCE).…”

The DNA repair endonuclease XPG interacts directly and functionally with the WRN helicase defective in Werner syndrome

“…53,54 Further, WRN-deficient cells undergo rapid replicative senescence without accelerated telomere shortening but with aberrant telomeric structures, including increased telomere associations and telomere sister chromatid exchanges and loss of the G-rich lagging strand DNA. 37,41 These data suggest that telomere dysfunction is one cause of the observed genomic instability and premature aging observed in WS. It is possible that the interaction of XPG with WRN is functionally important in telomere maintenance, and so it will be of interest to learn whether XPG has a role at telomeres in S phase.…”

“…37 Loss of WRN leads to increased chromosome aberrations, defective resolution of Holliday junctions, abnormal DNA replication intermediates, large deletions and increased incidence of telomere sister chromatid exchange. [37][38][39][40][41] Direct measurement of replication fork kinetics showed that, after DNA damage, replication fork progression was significantly slower in the absence of WRN.…”

Molecular insights into the heterogeneity of telomere reprogramming in induced pluripotent stem cells

“…iPSCs with haploinsufficiency of telomerase (Terc +/− ) show an increase in mean telomere length between P6 and P22, which coincides with increased heterogeneity (Supplementary information, Figure S3B), yet have much reduced expression levels of Dnmt3a, Dnmt3b and Suv39h2 ( 4B) at early passage and increased TSCE ( Figure 4A) at early-to-mid-passage, likely suggesting that recombination appears to be a response to the lack of active telomerase. However, excess telomere recombination by TSCE in telomerase-deficient cells also can cause accelerated cellular senescence [46]. Aberrant frequent telomere sister chromatid recombination, telomere loss and instability, together with insufficient reprogramming of iPSCs due to telomerase deficiency and abnormal epigenetic changes eventually lead to cell senescence as seen in Terc −/− iPSCs at late passages.…”