The transcription factor p53 is the most frequently impaired tumor suppressor in human cancers. In response to various stress stimuli, p53 activates transcription of genes that mediate its tumor-suppressive functions. Distinctive characteristics of p53 outlined here enable a well-defined program of genes involved in cell cycle arrest, apoptosis, senescence, differentiation, metabolism, autophagy, DNA repair, anti-viral response, and anti-metastatic functions, as well as facilitating autoregulation within the p53 network. This versatile, anti-cancer network governed chiefly by a single protein represents an immense opportunity for targeted cancer treatment, since about half of human tumors retain unmutated p53. During the last two decades, numerous compounds have been developed to block the interaction of p53 with the main negative regulator MDM2. However, small molecule inhibitors of MDM2 only induce a therapeutically desirable apoptotic response in a limited number of cancer types. Moreover, clinical trials of the MDM2 inhibitors as monotherapies have not met expectations and have revealed hematological toxicity as a characteristic adverse effect across this drug class. Currently, combination treatments are the leading strategy for enhancing efficacy and reducing adverse effects of MDM2 inhibitors. This review summarizes efforts to identify and test therapeutics that work synergistically with MDM2 inhibitors. Two main types of drugs have emerged among compounds used in the following combination treatments: first, modulators of the p53-regulated transcriptome (including chromatin modifiers), translatome, and proteome, and second, drugs targeting the downstream pathways such as apoptosis, cell cycle arrest, DNA repair, metabolic stress response, immune response, ferroptosis, and growth factor signaling. Here, we review the current literature in this field, while also highlighting overarching principles that could guide target selection in future combination treatments.

• Keywords
• combination therapy, integrated stress response, nelfinavir, nutlin, p53, polytherapy,
• MeSH
• Molecular Targeted Therapy * MeSH
• Humans MeSH
• Tumor Suppressor Protein p53 * metabolism   genetics   antagonists & inhibitors   MeSH
• Neoplasms * drug therapy   metabolism   genetics   MeSH
• Antineoplastic Agents * therapeutic use   pharmacology   MeSH
• Proto-Oncogene Proteins c-mdm2 antagonists & inhibitors   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Tumor Suppressor Protein p53 * MeSH
• Antineoplastic Agents * MeSH
• Proto-Oncogene Proteins c-mdm2 MeSH

Protein phosphatase magnesium-dependent 1 delta (PPM1D) terminates the cell cycle checkpoint by dephosphorylating the tumour suppressor protein p53. By targeting additional substrates at chromatin, PPM1D contributes to the control of DNA damage response and DNA repair. Using proximity biotinylation followed by proteomic analysis, we identified a novel interaction between PPM1D and the shelterin complex that protects telomeric DNA. In addition, confocal microscopy revealed that endogenous PPM1D localises at telomeres. Further, we found that ATR phosphorylated TRF2 at S410 after induction of DNA double strand breaks at telomeres and this modification increased after inhibition or loss of PPM1D. TRF2 phosphorylation stimulated its interaction with TIN2 both in vitro and at telomeres. Conversely, induced expression of PPM1D impaired localisation of TIN2 and TPP1 at telomeres. Finally, recruitment of the DNA repair factor 53BP1 to the telomeric breaks was strongly reduced after inhibition of PPM1D and was rescued by the expression of TRF2-S410A mutant. Our results suggest that TRF2 phosphorylation promotes the association of TIN2 within the shelterin complex and regulates DNA repair at telomeres.

• MeSH
• Phosphorylation MeSH
• Humans MeSH
• DNA Damage MeSH
• Telomeric Repeat Binding Protein 2 * MeSH
• Telomere-Binding Proteins * metabolism   MeSH
• Proteomics MeSH
• Shelterin Complex * MeSH
• Telomere metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Telomeric Repeat Binding Protein 2 * MeSH
• Telomere-Binding Proteins * MeSH
• Shelterin Complex * MeSH
• TINF2 protein, human MeSH Browser

Genome integrity is protected by the cell-cycle checkpoints that prevent cell proliferation in the presence of DNA damage and allow time for DNA repair. The transient checkpoint arrest together with cellular senescence represent an intrinsic barrier to tumorigenesis. Tumor suppressor p53 is an integral part of the checkpoints and its inactivating mutations promote cancer growth. Protein phosphatase magnesium-dependent 1 (PPM1D) is a negative regulator of p53. Although its loss impairs recovery from the G2 checkpoint and promotes induction of senescence, amplification of the PPM1D locus or gain-of-function truncating mutations of PPM1D occur in various cancers. Here we used a transgenic mouse model carrying a truncating mutation in exon 6 of PPM1D (Ppm1dT). As with human cell lines, we found that the truncated PPM1D was present at high levels in the mouse thymus. Truncated PPM1D did not affect differentiation of T-cells in the thymus but it impaired their response to ionizing radiation (IR). Thymocytes in Ppm1dT/+ mice did not arrest in the checkpoint and continued to proliferate despite the presence of DNA damage. In addition, we observed a decreased level of apoptosis in the thymi of Ppm1dT/+ mice. Moreover, the frequency of the IR-induced T-cell lymphomas increased in Ppm1dT/+Trp53+/- mice resulting in decreased survival. We conclude that truncated PPM1D partially suppresses the p53 pathway in the mouse thymus and potentiates tumor formation under the condition of a partial loss of p53 function.

• Keywords
• cancer, cell-cycle checkpoint, protein phosphatase, tumor suppressor p53,
• MeSH
• Apoptosis * MeSH
• Cell Cycle MeSH
• Radiation, Ionizing MeSH
• Lymphoma metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Tumor Suppressor Protein p53 metabolism   MeSH
• Neoplasms, Radiation-Induced metabolism   MeSH
• DNA Repair MeSH
• DNA Damage MeSH
• Cell Proliferation MeSH
• Protein Phosphatase 2C physiology   MeSH
• Thymocytes cytology   metabolism   MeSH
• Thymus Gland * cytology   metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Tumor Suppressor Protein p53 MeSH
• Ppm1d protein, mouse MeSH Browser
• Protein Phosphatase 2C MeSH
• Trp53 protein, mouse MeSH Browser

Genotoxic stress triggers a combined action of DNA repair and cell cycle checkpoint pathways. Protein phosphatase 2C delta (referred to as WIP1) is involved in timely inactivation of DNA damage response by suppressing function of p53 and other targets at chromatin. Here we show that WIP1 promotes DNA repair through homologous recombination. Loss or inhibition of WIP1 delayed disappearance of the ionizing radiation-induced 53BP1 foci in S/G2 cells and promoted cell death. We identify breast cancer associated protein 1 (BRCA1) as interactor and substrate of WIP1 and demonstrate that WIP1 activity is needed for correct dynamics of BRCA1 recruitment to chromatin flanking the DNA lesion. In addition, WIP1 dephosphorylates 53BP1 at Threonine 543 that was previously implicated in mediating interaction with RIF1. Finally, we report that inhibition of WIP1 allowed accumulation of DNA damage in S/G2 cells and increased sensitivity of cancer cells to a poly-(ADP-ribose) polymerase inhibitor olaparib. We propose that inhibition of WIP1 may increase sensitivity of BRCA1-proficient cancer cells to olaparib.

• Keywords
• DNA repair, PARP inhibitor, chemotherapy, genotoxic stress, olaparib, phosphatase,
• MeSH
• Tumor Suppressor p53-Binding Protein 1 metabolism   MeSH
• Apoptosis drug effects   MeSH
• Drug Resistance, Neoplasm drug effects   MeSH
• Chromatin metabolism   MeSH
• Phthalazines pharmacology   MeSH
• HEK293 Cells MeSH
• Homologous Recombination genetics   MeSH
• G2 Phase Cell Cycle Checkpoints MeSH
• S Phase Cell Cycle Checkpoints MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Breast Neoplasms metabolism   MeSH
• DNA Repair genetics   physiology   MeSH
• Poly(ADP-ribose) Polymerase Inhibitors pharmacology   MeSH
• Piperazines pharmacology   MeSH
• DNA Damage genetics   physiology   MeSH
• Cell Proliferation drug effects   MeSH
• BRCA1 Protein metabolism   MeSH
• Protein Phosphatase 2C antagonists & inhibitors   genetics   metabolism   MeSH
• Antineoplastic Agents pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Tumor Suppressor p53-Binding Protein 1 MeSH
• BRCA1 protein, human MeSH Browser
• Chromatin MeSH
• Phthalazines MeSH
• olaparib MeSH Browser
• Poly(ADP-ribose) Polymerase Inhibitors MeSH
• Piperazines MeSH
• PPM1D protein, human MeSH Browser
• BRCA1 Protein MeSH
• Protein Phosphatase 2C MeSH
• Antineoplastic Agents MeSH
• TP53BP1 protein, human MeSH Browser