Phosphorylation-Dependent Pin1 Isomerization of ATR: Its Role in Regulating ATR’s Anti-apoptotic Function at Mitochondria, and the Implications in Cancer

Abstract

Peptidyl-prolyl isomerization is an important post-translational modification of protein because proline is the only amino acid that can stably exist as cis and trans, while other amino acids are in the trans conformation in protein backbones. This makes prolyl isomerization a unique mechanism for cells to control many cellular processes. Isomerization is a rate-limiting process that requires a peptidyl-prolyl cis/trans isomerase (PPIase) to overcome the energy barrier between cis and trans isomeric forms. Pin1, a key PPIase in the cell, recognizes a phosphorylated Ser/Thr-Pro motif to catalyze peptidyl-prolyl isomerization in proteins. The significance of the phosphorylation-dependent Pin1 activity was recently highlighted for isomerization of ATR (ataxia telangiectasia-and Rad3-related). ATR, a PIKK protein kinase, plays a crucial role in DNA damage responses (DDR) by phosphorylating hundreds of proteins. ATR can form cis or trans isomers in the cytoplasm depending on Pin1 which isomerizes cis-ATR to trans-ATR. Trans-ATR functions primarily in the nucleus. The cis-ATR, containing an exposed BH3 domain, is anti-apoptotic at mitochondria by binding to tBid, preventing activation of pro-apoptotic Bax. Given the roles of apoptosis in many human diseases, particularly cancer, we propose that cytoplasmic cis-ATR enables cells to evade apoptosis, thus addicting cancer cells to cis-ATR formation for survival. But in normal DDR, a predominance of trans-ATR in the nucleus coordinates with a minimal level of cytoplasmic cis-ATR to promote DNA repair while preventing cell death; however, cells can die when DNA repair fails. Therefore, a delicate balance/equilibrium of the levels of cis-and trans-ATR is required to ensure the cellular homeostasis. In this review, we make a case that this anti-apoptotic role of cis-ATR supports oncogenesis, while Pin1 that drives the formation of trans-ATR suppresses tumor growth. We offer a potential, novel target that can be specifically targeted in cancer cells, without killing normal cells, to significantly reduce the adverse

Selective 1Hα NMR Methods Reveal Functionally Relevant Proline cis/trans Isomers in Intrinsically Disordered Proteins: Characterization of Minor Forms, Effects of Phosphorylation, and Occurrence in Proteome

“…[1][2] These systems display an ensemble of conformations instead of ap ermanent secondary structure.T he conformational flexibility enables them to bind to multiple targets and to become potential drug targets. [3][4][5] One factor contributing to the conformational heterogeneity is the cis/trans isomerization of proline (Pro) residues.T he different cis/trans-Pro states are associated with tumorigenesis (in p53TAD [6] and ATR [7] ), the formation of neurodegenerative diseases (in tau [8] and a-synuclein [9] )and in circadian rhythm regulation. [10] Previous studies suggested that the different isomeric forms can inhibit or support protein-protein interactions.…”

GM-CSF and IL-33 Orchestrate Polynucleation and Polyploidy of Resident Murine Alveolar Macrophages in a Murine Model of Allergic Asthma

“…In line with that, we observed a decrease in the phosphorylation status of p53 in tAMs stimulated in vitro with GM-CSF, suggesting that upon GM-CSF exposure, the cells are permissive to cell division although DNA damage might be present. Similarly, ATR expression and function may be uncoupled from its mRNA expression via modulation of its phosphorylation status, in particular in the control of DNA damage associated with cell death [ 54 ] or its isomeric status [ 55 ]. In contrast, MafB expression increased upon in vivo HDM exposure.…”

Mitochondrial cytochrome c shot towards histone chaperone condensates in the nucleus

“…The DNA damage response (DDR), mediated by p53, eventually activates proteins such as PUMA (p53 upregulated modulator of apoptosis), BAX (Bcl‐2‐associated X protein) and BAK (Bcl‐2 homologous antagonist/killer), thereby yielding the release of pro‐apoptotic factors from mitochondria [6]. Notably, one of the three known DDR early sensors, the ataxia telangiectasia and Rad3‐related (ATR) protein, plays a dual role depending on its isomerization state: one state aids the onset of DDR upstream of p53 in the cell nucleus and the other state plays a protective role against pro‐apoptotic stimuli in mitochondria [7]. This illustrates how mitochondrial reactions can be modulated during the DDR response, but does not imply a direct involvement of mitochondrial proteins in regulation of nuclear DNA repair or DDR.…”