Mateusz Hess: A tailored phospho-p53 library probes antibody specificity and recognition limitations

[1] Among these, phosphorylation plays a crucial role in modu-lating p53 activity, stability, and interactions with key regu-latory partners. [2] The N-terminal transactivation domain 1(TAD1) of p53 is a hotspot for phosphorylation, harboringseven serine/threonine residues that are dynamically modi-fied in response to cellular stress.

These phosphorylation events have been implicated invarious aspects of p53 regulation. Phosphorylation of Ser15by ATM kinase is the most commonly described modifica-tion and is believed to initiate the p53 response to DNAdamage. [3–6] Subsequently, p53 is phosphorylated by CK1on Thr18 which stabilises p53 by reducing its interactionwith the negative regulator MDM2. [7–9] Phosphorylationsat Ser20 and Ser37 have also been shown to enhance p53activity, in part by enhancing p53’s interaction with theacetyltransferases p300 and CBP. [10,11] Closer to the veryN-terminus, phosphorylation of Ser6 and Ser9 has been implicated.

in TGF-β signalling and may play a role in sta-bilisation of p53 mediated by the chaperonin system. [12–14]A more complex picture is presented by phosphorylation ofSer33 which creates a binding site for the phosphorylation-dependent prolyl isomerase Pin1, in turn enhancing p53activity. [15,16] Despite this knowledge, a complete under-standing of how these individual phosphorylation eventscontribute to p53 regulation remains elusive due to the mul-titude of p53-interacting proteins, the interplay between co-occurring phosphorylation marks and their potential to trig-ger accumulation of further PTM signatures throughout theprotein.

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