Figure 9.

Speculative model of TERRA, hnRNP A1, and hTR/DNA-PKcs interactions at telomeres. The presence of “free” hTR (not associated with TERRA) stimulates DNA-PKcs phosphorylation of hnRNP A1, an event that contributes to the removal of TERRA from telomeres and may be especially important at leading-strand telomeres due to sequence complementary with TERRA. hnRNP A1 shuttling of TERRA off telomeres and out of the nucleus to the cytoplasm may aid the NMD pathway of TERRA degradation and serve to regulate TERRA levels in a cell cycle dependent manner. This supposition is supported by previous demonstrations of SMG1 stimulation and UPF1 action at leading-strand telomeres (Chawla et al., 2011). As TERRA is also complementary to hTR, when TERRA levels are low in S-phase, hnRNP A1 may also aid in the recruitment of hTR to its 3′ single-stranded overhang/substrate on newly replicated lagging-strand telomeres. When TERRA levels are high (e.g., in G1), sequestration of hTR by TERRA limits TERRA localization to telomeres, and influences the balance of free to telomere-bound TERRA.