Introduction: One of the hallmark features of cancers is their genomic instability, which is associated with an increased propensity for DNA damage accumulation. The DNA damage response (DDR) related proteins leading to the cell cycle arrest were inactivated due to dephosphorylation by some phosphatases, so the cell cycle returned to its pre-stress state (normal conditions). PPM1D (Protein phosphatase 1D), also known as wild-type p53-induced phosphatase 1 (Wip1) or protein phosphatase 2C delta (PP2Cδ), is one of the most important Ser/Thr DDR phosphatases and exerts suppression of several signaling pathways within DDR (as a negative regulator) through affecting the activity of its downstream targets i.e., tumor suppressors in a p53-dependent manner. The role of Wip1 in the proliferation of stem cells and the regulation of T- and B-cell maturations and inflammation was also proposed. Therefore, Wip1 is known as a growth-promoting phosphatase and may be an oncoprotein. The encoding gene (PPM1D) is located on chromosome 17q23. In many high-risk human cancers, such as liver, ovarian, breast, lung, skin, pancreatic, brain, and different types of blood cancers, the PPM1D gene plays an oncogenic role. Studying and investigating the molecular mechanism of Wip1 and its role in cancer is important because these studies ultimately can clarify the etiology of cancer, and also open the way to introduce new candidates for cancer diagnosis, prognosis, and even treatment.
Methods: This study was conducted using the studies published in databases such as PubMed, Google Scholar, and Sci-hub from 1996 to 2024. The search focused on key terms such as ‘wip1 phosphatase,’ ‘PPM1D gene,’ ‘DNA damage response’, and ‘human tumorigenesis.’ The content aimed to comprehensively collect information related to common human cancers from a molecular perspective, particularly emphasizing the oncogenic role of cellular phosphatases.
Results: Different types of cellular stress such as single-stranded DNA (ssDNA) and DNA double-strand breaks (DSBs) activated the ATR/CHK1 as well as ATM/ CHK2 pathways, respectively. In fact, the role of ATM and ATR is phosphorylation and activation of the effector checkpoint kinases i.e., CHK2 and CHK1. Consequently, the p53 protein is modified post-translationally by ATR/CHK1 and ATM/CHK2, leading to its stabilization and oligomerization. The protein P53 as a tumor suppressor is an important molecule that interconnects DDR, cell cycle checkpoints, and also cell fate decisions. In addition, this protein stimulates the expression of WIP1 and Mdm2 as its negative regulators. WIP1 inactivates the p53 pathway after accumulating sufficient protein levels and terminates the DDR. WIP1 also dephosphorylates MDM2 which leads to its stabilization and the degradation of P53. It can be said that the main role of WIP1 is to inhibit the stability of P53 by increasing the stability of MDM2.
WIP1, like other members of the PPM/PP2C family, is a monomeric enzyme (605 amino acids) that requires divalent cations, primarily Mg2+ or Mn2+, for catalytic effectiveness. The PPM1D structure includes a large flap subdomain with 76 residues (P219-D295) adjacent to the active site. The flap region consists of two short α-helices (α3 and α4) and three short β-strands (β9, β10, and β11) followed by an irregular loop. In the crystal structure of PPM1D, extra electron density was observed for an unidentified atom between the nitrogen of the Lys336 side chain and the sulfur of Cys346, with 100% occupancy. Competitive modifications suggest this atom is oxygen, indicating a covalent cross-link that connects Lys336 and Cys346 through a nitrogen-oxygen-sulfur (NOS) bridge. The formation of the Lys336-Cys346 NOS cross-link may preserve PPM1D activity under high oxidative potential conditions, such as in cancer cells or following exposure to ionizing radiation.
Conclusion: Since WIP1 acts as an important negative regulator of p53 and a terminator of DDR, its overexpression inhibits p53 function and contributes to tumorigenesis, while loss or downregulation of this protein can significantly delay tumor growth in mice. Therefore, the use of RNA interference drugs affecting this pathway can reactivate the p53 pathway and inhibit proliferation in tumors with p53. It is hoped that with further studies on the PPM1D gene, more successes in cancer treatment or control will occur in the future.
Keywords: DNA damage response, Phosphatase, PPM1D gene, Tumor suppressor, WIP1