Editing P53 (section)

=== DNA damage and repair ===
p53 plays a role in regulation or progression through the cell cycle, [[apoptosis]], and [[Genome instability|genomic stability]] by means of several mechanisms:
* It can activate [[DNA repair]] proteins when DNA has sustained damage<ref name="Ana et al">{{cite journal | vauthors = Janic A, Abad E, Amelio I | title = Decoding p53 tumor suppression: a crosstalk between genomic stability and epigenetic control? | journal = Cell Death and Differentiation | volume = 32 | issue = 1 | pages = 1–8 | date = January 2025 | pmid = 38379088 | pmc = 11742645 | doi = 10.1038/s41418-024-01259-9 | doi-access = free }}{{Creative Commons text attribution notice|cc=by4|from this source=yes}}</ref> Thus, it may be an important factor in [[aging]].<ref>{{cite book | vauthors = Gilbert SF |title=Developmental Biology, 10th ed. |publisher=Sinauer Associates, Inc. Publishers |location=Sunderland, MA USA |pages=588}}</ref>
* It can arrest growth by holding the [[cell cycle]] at the [[G1/S transition|G1/S regulation point]] on DNA damage recognition—if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle.
* It can initiate apoptosis (i.e., [[programmed cell death]]) if DNA damage proves to be irreparable.
* It is essential for the [[Cellular senescence|senescence]] response to short [[telomere]]s.

[[File:P53 pathways.jpg|300px|right|thumb|'''p53 pathway''': In a normal cell, p53 is inactivated by its negative regulator, mdm2. Upon DNA damage or other stresses, various pathways will lead to the dissociation of the p53 and mdm2 complex. Once activated, p53 will induce a cell cycle arrest to allow either repair and survival of the cell or apoptosis to discard the damaged cell. How p53 makes this choice is currently unknown.]]

WAF1/CIP1 encodes for [[p21]] and hundreds of other down-stream genes. p21 (WAF1) binds to the [[G1 phase|G1]]-[[S phase|S]]/[[Cyclin-dependent kinase|CDK]] ([[CDK4]]/[[CDK6]], [[CDK2]], and [[CDK1]]) complexes (molecules important for the [[G1/S transition]] in the cell cycle) inhibiting their activity. {{cn|date=November 2024}}

When p21(WAF1) is complexed with CDK2, the cell cannot continue to the next stage of cell division. A mutant p53 will no longer bind DNA in an effective way, and, as a consequence, the p21 protein will not be available to act as the "stop signal" for cell division.<ref name="urlThe p53 tumor suppressor protein">{{cite book | chapter-url = https://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=gnd.section.107 | chapter = Skin and Connective Tissue | title = Genes and Disease |author=National Center for Biotechnology Information |publisher=United States National Institutes of Health |access-date=2008-05-28 |year=1998}}</ref> Studies of human embryonic stem cells (hESCs) commonly describe the nonfunctional p53-p21 axis of the G1/S checkpoint pathway with subsequent relevance for cell cycle regulation and the DNA damage response (DDR). Importantly, p21 mRNA is clearly present and upregulated after the DDR in hESCs, but p21 protein is not detectable. In this cell type, p53 activates numerous [[microRNA]]s (like miR-302a, miR-302b, miR-302c, and miR-302d) that directly inhibit the p21 expression in hESCs. {{cn|date=November 2024}}

The p21 protein binds directly to cyclin-CDK complexes that drive forward the cell cycle and inhibits their kinase activity, thereby causing cell cycle arrest to allow repair to take place. p21 can also mediate growth arrest associated with differentiation and a more permanent growth arrest associated with cellular senescence. The p21 gene contains several p53 response elements that mediate direct binding of the p53 protein, resulting in transcriptional activation of the gene encoding the p21 protein. {{cn|date=November 2024}}
[[File:Activation of p53 in response to stress signals initiates its transcriptional activity, leading to the activation of cellular protective pathways.jpg|thumb|Activation of p53 in response to stress signals initiates its transcriptional activity, leading to the activation of cellular protective pathways<ref name="Ana et al"/>

p53 binds to the DNA in a tetrameric configuration and promotes the transcription of a wide array of genes. Pictured are key p53 pathways and transcriptional targets regulated by p53 with a specific emphasis on p53-dependent DNA repair genes. BER (base excision repair), NER (nucleotide excision repair), MMR (mismatch repair), HR (homologous recombination), NHEJ (non-homologous end-joining), DDR (DNA damage repair)]]
The p53 and [[Retinoblastoma protein|RB1]] pathways are linked via p14ARF, raising the possibility that the pathways may regulate each other.<ref name="pmid9744267">{{cite journal |vauthors=Bates S, Phillips AC, Clark PA, Stott F, Peters G, Ludwig RL, Vousden KH |title=p14ARF links the tumour suppressors RB and p53 |journal=Nature |volume=395 |issue=6698 |pages=124–5 |date=September 1998 |pmid=9744267 |doi=10.1038/25867 |bibcode=1998Natur.395..124B |s2cid=4355786}}</ref>

p53 expression can be stimulated by UV light, which also causes DNA damage. In this case, p53 can initiate events leading to [[sun tanning|tanning]].<ref>{{cite magazine |title=Genome's guardian gets a tan started |url=https://www.newscientist.com/channel/health/mg19325955.800-genomes-guardian-gets-a-tan-started.html |magazine=New Scientist |date=March 17, 2007 |access-date=2007-03-29}}</ref><ref name="pmid17350573">{{cite journal |vauthors=Cui R, Widlund HR, Feige E, Lin JY, Wilensky DL, Igras VE, D'Orazio J, Fung CY, Schanbacher CF, Granter SR, Fisher DE |title=Central role of p53 in the suntan response and pathologic hyperpigmentation |journal=Cell |volume=128 |issue=5 |pages=853–64 |date=March 2007 |pmid=17350573 |doi=10.1016/j.cell.2006.12.045 |doi-access=free}}</ref>