FIGURE 5.

Model of TAPR1 modulation of p53 signaling in response to telomere erosion. (a) In the absence of sufficient telomere‐replenishing activity (e.g. telomerase inhibition), telomeres progressively erode and eventually induce a DNA damage response, resulting in p53 activation and induction of transcriptional targets such as CDKN1a/p21. (b) TAPR1 attenuates p53 activation in the pre‐B cell line NALM‐6. Proximity labeling identified HUWE1, an E3 ubiquitin ligase that targets p53 for degradation, as an interaction partner with TAPR1. Whether TAPR1 attenuates p53 in a HUWE1‐dependent manner has not yet been determined. (c) Deletion of TAPR1 leads to excessive p53 induction and increased sensitivity of cells treated with the MDM2 inhibitor nutlin‐3a or the DNA damaging agent doxorubicin, and a synthetic/sick/lethal (SSL) phenotype in cells either deleted for telomerase (TERT) or treated with the telomerase inhibitor BIBR1532. TAPR1 may also limit p53 activation in other circumstances including DNA damage, senescence and cancer