TRF2 Upregulates Protein Phosphatase 2A Subunit PPP2R2C to Attenuate DNA Damage Response at Telomeres and Pericentromeres Upon Replicative Stress

Telomeres and pericentromeres are regions of heterochromatin that are difficult to replicate. Telomeric binding factor 2 (TRF2) is a key telomere protective protein that acts against DNA damage at telomeres and allows the progression of replication forks through telomere chromatin, a region with heterochromatin features that is difficult to replicate. TRF2 is also required at pericentromeres for proper replication elongation. Here, we show that TRF2 positively regulates the activity of protein phosphatase 2A (PP2A) by activating the expression of PPP2R2C, a gene encoding an isoform of the regulatory subunit of PP2A with particularly elevated expression in neuronal tissues. Mechanistically, we provide evidence that TRF2 binds to an intronic interstitial telomeric sequence (ITS) of PPP2R2C with transactivation activity. Moreover, PPP2R2C is recruited to telomeres and pericentromeres during S phase and during replicative stress where it attenuates the DNA damage response. Finally, we show that the TRF2-dependent regulation of PPP2R2C expression plays an important role in maintaining neurodevelopment in zebrafish. These results reveal a mechanism required for normal neurodevelopment by which TRF2 attenuates DNA damage by upregulating PPP2R2C, thereby stimulating PP2A activity at two regions difficult to replicate: telomeres and pericentromeres.