p21: A Two-Faced Genome Guardian

In normal cells, p21 maintains its genuine signature function as a cell cycle inhibitor and antiproliferative effector. p21 can mediate cellular senescence via p53-dependent and -independent pathways. While p21 mediates cellular senescence, it appears to exert opposing effects, mostly inhibitory, but sometimes stimulatory, on various DNA repair pathways, such as base excision (BER) and nucleotide excision (NER) repair. In cells with complex DNA damage comprising double-strand breaks (DSBs) and damaged bases in close proximity to each other, evidence indicates that p21 is recruited to damaged sites, specifically DSBs, colocalizing with DSB repair proteins to facilitate their repair. p21 is a two-faced regulator depending on cell type, cellular localization, p53 status, and the type and level of genotoxic stress. It can acquire either oncosuppressive or oncopromoting properties depending on whether it is in a p53-proficient or p53-deficient environment, respectively. Under a state of combined p53-deficiency and p21 constitutive expression, a subset of cells can escape senescence and acquire an aggressive and chemotherapy drug-resistant cancer phenotype with elevated genomic instability (‘escape’ cells). Upon DNA damage or other stressors, the tumor suppressor p53 is activated, leading to transient expression of the cyclin-dependent kinase inhibitor (CKI) p21. This either triggers momentary G1 cell cycle arrest or leads to a chronic state of senescence or apoptosis, a form of genome guardianship. In the clinic, the presence of p21 has been considered an indicator of wildtype p53 activity. However, recent evidence suggests that p21 also acts as an oncogenic factor in a p53-deficient environment. Here, we discuss the controversial aspects of the two-faced involvement of p21 in cancer and speculate on how this new information may increase our understanding of its role in cancer pathogenesis. Prevailing notions indicate that p21 might also act as antiapoptotic agent, which may have relevant implications for future therapeutic strategies. Upon DNA damage or other stressors, the tumor suppressor p53 is activated, leading to transient expression of the cyclin-dependent kinase inhibitor (CKI) p21. This either triggers momentary G1 cell cycle arrest or leads to a chronic state of senescence or apoptosis, a form of genome guardianship. In the clinic, the presence of p21 has been considered an indicator of wildtype p53 activity. However, recent evidence suggests that p21 also acts as an oncogenic factor in a p53-deficient environment. Here, we discuss the controversial aspects of the two-faced involvement of p21 in cancer and speculate on how this new information may increase our understanding of its role in cancer pathogenesis. Prevailing notions indicate that p21 might also act as antiapoptotic agent, which may have relevant implications for future therapeutic strategies. in cases of single-strand DNA damage, BER mediates the processing of base and/or abasic lesions. It is initiated by one of many specialized DNA glycosylases, which recognize and catalyze the removal of damaged bases. BER performs the processing of DNA lesions via two major pathways: the short-patch BER (SP-BER) processes one single nucleotide, while long-patch BER (LP-BER) processes more than two nucleotides. an anticancer cytotoxic drug used in the treatment of Hodgkin's and nonHodgkin's lymphoma, melanoma, squamous cell cancers, sarcoma, testicular cancer, ovarian cancer, and others. Bleomycin is considered a ‘radiomimetic’ due to its ability to induce complex DNA damage, such as DNA double-strand breaks (DSBs) arising from the formation of two vicinal DNA strand breaks and base lesions. phenomenon by which cells cease to divide. They no longer replicate but remain metabolically active. Senescence may have a replicative origin due to telomere shortening or as a result of excessive DNA damage. It is generally accepted that oncogene-induced senescence due to oxidative DNA damage and replication errors is part of the tumorigenesis barrier enforced by DNA damage checkpoints. a chemotherapy drug used to treat many cancers (breast, bladder, cervical, head and neck, ovarian, testicular, etc.). Cisplatin interferes with DNA replication by targeting the most rapidly proliferating cells (often cancer cells). It crosslinks DNA and the cisplatin–DNA adducts are primarily processed by nucleotide excision repair (NER). Cisplatin resistance is often associated with NER mutations. specific inheritable chromosomal regions prone to forming gaps or breaks on metaphase chromosomes in cells under replication stress. The most typical inducer of CFSs is the antibiotic aphidicolin, an inhibitor of DNA polymerase. CFSs are considered a normal part of the human genome and are relatively stable when not under replicative stress. proteins that inhibit cyclin-dependent kinases and suppress cell cycle progression. In general, they have key roles in coordinating cell proliferation and development, and usually function as tumor suppressor genes. p21 is considered a traditional CKI; other examples include p15, p16, p18, p19, p27, and p57. protein complex involved in the regulation of cell cycle-dependent gene expression. It is evolutionarily conserved, although its synthesis varies from species to species. DREAM facilitates gene repression during the G0 quiescent phase and coordinates periodic gene expression with peaks during the G1/S and G2/M phases. Key components are proposed to include the proteins RBL1 (p107) and RBL2 (p130), both of which are homologs of RB (p105), usually binding E2F transcription factors. a multicomponent response network activated when the level of DNA damage and/or replication impediments exceeds a certain threshold. The two protein kinases, ataxia-telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3 related (ATR), act as signaling components, activating protein kinases CHK1 and CHK2, among other targets. Together with ATM and ATR, CHK1 and CHK2 decrease cyclin-dependent kinase (CDK) activity, often mediated by the activation of the p53 transcription factor. The result of these combined DNA damage response and repair pathways (DDR/R) is the coordinated arrest of cell cycle progression and the initiation of various DNA repair pathways, depending on the type of DNA damage. neighboring breaks in both strands of the DNA helix. Repair occurs via two major pathways: the faithful homologous recombination (HR) pathway and the more error-prone nonhomologous end-joining (NHEJ) pathway. In addition, ATM and ATR rapidly phosphorylate many histone H2AX molecules adjacent to the DSB site (γ-H2AX), which together, act as a focus for the recruitment of myriad DNA and chromatin repair factors, increasing the efficiency of DSB repair. when DNA lesions are not repaired and the cell enters replication, the TLS pathway is activated as a DNA damage-tolerance but error-prone response pathway. To bypass the DNA lesions blocking DNA replications, specialized TLS DNA polymerases are recruited to the site (e.g., Y family of polymerases). TLS or bypass polymerases are capable of DNA synthesis over the damaged DNA; conventional replicative DNA polymerases then resume normal DNA synthesis. after the S phase, cells enter the G2 phase, where repair of DNA lesions might occur, along with the preparation of mitosis in M phase. The G2–M DNA damage checkpoint in eukaryotic organisms is important in ensuring that cells do not enter mitosis (cell cycle arrest) before damaged DNA is repaired after replication. Cells with a defective G2–M checkpoint will enter mitosis without completing repair, usually leading to cell death following cell division, or to enhanced chromosomal instability. p53 can halt the cell cycle: this G2-checkpoint involves the inhibition of Cdc2, a CDK required to enter mitosis. technology using the most current genome-wide data obtained, (e.g., analyzing whole-genome sequencing or widespread transcriptomic or metabolomic data). a family of protease enzymes with pivotal roles in programmed cell death (apoptosis). Initiator caspases (caspase 2, caspase 8, and caspase 9) are the apical caspases in apoptotic signaling cascades. Initiator caspases, such as caspase 8, are autoproteolytically cleaved, initiating apoptosis. a rare, autosomal dominant, hereditary disorder where carriers, particularly children and young adults, have a predisposition towards developing various types of cancer. also known as Cdc10-dependent transcript factor 1 (CDT1) and cell division cycle 6 (CDC6): they allow only one round of DNA replication per cell cycle. They are part of the pre-replication complex (pre-RC) and allow an origin of replication (ORC) so that DNA replication can be initiated at that site. corrects DNA base pair mismatches during DNA replication, thereby averting mutations from becoming stable in dividing cells. Since MMR reduces the number of replication-associated errors, defects in MMR increase the spontaneous mutation rate. precursor of the natural antioxidant glutathione (GSH). The thiol (sulfhydryl) group is able to scavenge a variety of free radicals, thus conferring antioxidant properties. When taken internally, it replenishes intracellular levels of GSH. It is often used as a treatment against acetaminophen toxicity and acute liver failure, or also as an anti-inflammatory agent. handles the processing of helix-distorting (bulk) lesions, such as ultraviolet (UV)-induced or cisplatin-DNA adducts; many subpathways exist. oncogene-induced production of ROS in cells is considered an essential aspect of oncogene expression and a vital step in cellular transformation. ROS may act on mitogenic signaling molecules stimulating cellular hyperproliferation or may be genotoxic, activating DDR to halt proliferation and induce senescence. a chemotherapy drug based on platinum, currently used to treat colorectal, esophageal, and stomach cancer; it has been tested in research trials for several other cancers. a toroidal-shaped protein that encloses DNA and slides bi-directionally along the helix (sliding DNA clamp). It has diverse cellular roles, acting as a processivity factor for DNA polymerase δ in eukaryotic cells and also as a protein recruitment mediator. It is implicated in nucleic acid metabolism and is considered a pivotal component of the replication and DNA repair machinery. these cells synthesize extracellular matrix components and collagen, forming a structural basis for all animal tissues, the so-called ‘stroma’. In the case of breast, prostate, and pancreatic cancers, these fibroblasts support tumor epithelial growth and invasion, often referred as ‘cancer stroma’. TRAIL induces cell death in tumor cells by binding to specific death receptors, such as DR4 or TRAIL receptor 1. major mechanisms for protein catabolism in the mammalian cytosol and nucleus. These pathways are essential to the regulation of many cellular processes, including, but not limited to, apoptosis, cell cycle and cell division, DNA transcription and repair, response to extracellular stress, and so on. The addition of a chain of multiple copies of ubiquitin labels a protein for destruction by the intracellular protease, known as the 26S proteasome (proteosomal degradation).