tp53 ( tumor protein p53 ) is the paradigm of tumor suppressors and the most frequently mutated gene in cancer ( present in about 50% of cancers ) . alteration of the p53 gene is often associated with environmental mutagens such as ultraviolet ( uv ) light or smoking . as a result of sun exposure , the incidence of p53 mutations is strikingly high in skin squamous carcinomas ( 8090% ) . in spite of these numbers , the role of p53 in human tissue renewal , including epidermal homeostasis , remains intriguing . since experimenting in humans in vivo is not possible for obvious reasons , mouse models have become a strong reference for skin research . however , as observed for other key genes , p53 knockout ( ko ) mice develop normally . in addition , mouse and human skin displays different physiological features . to address the role of p53 in human skin using new approaches , we have adapted the shrna technology for the inactivation of endogenous proteins in human primary keratinocytes . we describe the consequences of silencing p53 in these epidermal cells in a recent issue of cell reports . we can now achieve efficiencies of about 90% for cell transduction with lentiviral vectors , which is the closest we can get to human ko epidermis . in steady - state healthy epidermis , p53 is thought to play a role in cell differentiation . however , contrary to our expectations , we found that knockdown of p53 in human keratinocytes favored squamous differentiation . we have proposed a novel model of the keratinocyte epidermal cell cycle in which differentiating cells do not undergo quiescence but instead continue post - mitotic dna replication in the absence of cell division ( endoreplication ) . mitotic slippage. this term is somewhat controversial but in our opinion it expresses well the following sequence of events that occur during endoreplication : ( 1 ) in the case of difficulty or danger , mitotic checkpoints block cell division ; ( 2 ) these cells are unable to properly stay in mitosis ( g2/m ) ; ( 3 ) as a result , they  slip through the g2/m checkpoints and restart dna replication ; ( 4 ) however , as the cells can not divide , they become polyploid . endoreplication is controversial within the field of skin biology because it is still a poorly understood concept despite some very good reviews that highlight its biological importance . defining endoreplication and explaining its potential functions is often a challenge . nonetheless , endoreplication might be more widespread in human tissues than we think . we have shown that in keratinocytes mitotic slippage occurs in response to cell cycle deregulation that causes dna replication errors (  replication stress ) and triggers mitotic checkpoints . our current paper in cell reports we believe that we answer 2 questions regarding epidermal homeostasis : ( 1 ) the function of p53 in normal keratinocytes ; and ( 2 ) the importance of endoreplication against precancerous mutations . p53 is upregulated by uv irradiation and is thought to trigger apoptosis of sunburn cells but , as mentioned above , we also overexpressed a temperature - sensitive form of p53 that behaves as an inactive mutation at 39c or as the active wild - type protein at 32c . similar to our observations for the knockdown , overexpression of the inactive conformation triggered terminal differentiation . p53 is a critical keeper of cell cycle pace , thus its absence caused cell cycle deregulation leading to replication stress , mitotic slippage , and endoreplication . this in turn triggered squamous differentiation , therefore forcing mutant cells to detach ( fig .  1 ) . interestingly , at 32c the wild - type conformation attenuated differentiation , indicating that p53 protects the proliferative compartment and putatively the stem cells . p53 surveys for correct execution of the cell cycle in epidermal homeostasis ( a ) . loss of p53 function as a single mutation causes mitotic slippage , squamous differentiation , and cell shedding , thus maintaining homeostasis ( b ) , or contributes to malignancy when additional mutations ( m2 ) affect cell division control and allow p53-deficient cells to divide ( c ) . p53 surveys for correct execution of the cell cycle in epidermal homeostasis ( a ) . loss of p53 function as a single mutation causes mitotic slippage , squamous differentiation , and cell shedding , thus maintaining homeostasis ( b ) , or contributes to malignancy when additional mutations ( m2 ) affect cell division control and allow p53-deficient cells to divide ( c ) . mitotic slippage , replication stress , and endoreplication are all fairly new concepts that we will probably read increasingly more about in the near future as they most likely have a role in cancer . we propose that these events represent a mitosis - differentiation checkpoint ( mdc ) , a tool used by normal skin to remove precancerous cells bearing irreparable damage . even though skin carcinomas are the most common malignancies , their incidence seems low considering that cells in the epidermis are continuously dividing and are chronically exposed to the mutagenic power of uv light . therefore , the skin must have powerful protective mechanisms in play when the level of pigment ( melanin ) is not sufficient and the dna repair machinery can not repair the damage produced . mutations of p53 are highly frequent in skin carcinomas yet we propose the existence of a protective mechanism in normal skin . how can both concepts be reconciled ? inactivation of p53 in the whole mouse did not provoke early skin carcinomas although the animals died by 4 months of age from other types of cancer . however , skin - specific p53 ko mice did develop squamous cell carcinomas from 4 months onwards . it therefore seems likely that additional mutations are required for the loss of p53 to be tumorigenic . our model proposes a second  guardian of the genome  through the cell division block imposed by the mdc . if this checkpoint is mutated , the additional absence of p53 , the original guardian of the genome , makes those cells more malignant ( fig .  1 ) . our data point to a homeostatic maintenance role of endoreplication that might be common to other endoreplicating tissues . the list of these tissues in the human body has increased to include megakaryocytes , hepathocytes , endometrium , keratinocytes , and cardiomyocytes and may expand further in the future . finally , we interpret our data to mean that skin carcinoma cells are malignant not simply because their cell cycle is deregulated but because , in addition , they are able to divide . we apologize that we could not cite every relevant publication because of length limitations ; many missing articles are cited within the papers we do list . we thank the instituto de salud carlos iii for their support , grant fis pi11/02070 .