More than half of all cancers have mutations in a gene called p53. The protein made from this gene is whats called a tumor suppressor: When working properly, it guards against cancer development in part, by detecting damaged DNA and alerting cells to repair it.
Cells without working p53 are unable to properly repair damaged DNA, leading to a buildup of mutations, including large chromosomal alterations. Because of its important role in maintaining DNA integrity, scientists long ago dubbed p53 the guardian of the genome.
But 30 years on from that christening, many questions remain about exactly how p53 guards the genome and how its loss promotes cancer.
One hotly debated question has been whether the guardian role of p53 is important for preventing cancer. While tumors with p53 mutations show evidence of chromosomal alterations, research has shown that the normal p53 protein controls several other processes that might explain why its inactivation promotes cancer. For example, p53 promotes apoptosis, or programmed cell death, in cells that have developed precancerous features.
Another question relates to how the genetic instability arises following p53 loss. One longstanding assumption has been that p53 loss acts as a kind of gateway to genetic chaos. In other words, losing the tumor suppressor leads to random buildup of genetic mutations without much rhyme or reason. But a new study from researchers at the Sloan Kettering Institute (SKI) challenges that assumption and brings some insight into p53s guardian role.
Rather than promoting genetic chaos, what we see when cells lose p53 is an orderly progression of genetic changes that is actually quite predictable, says Scott Lowe, Chair of the Cancer Biology and Genetics Program in SKI and the senior author on the study, which was published August 17, 2022, in the journal Nature. That came as a complete surprise to us and suggests a new way to think about possibly treating cancer.
Scientists have struggled to fully understand p53s role in cancer, particularly its effects on the genome, in part because there are few good laboratory models that allow the study of p53 function at the earliest (benign) stages of tumor development, well before cells have acquired obvious cancerous properties.
By staining cells taken from mouse models, researchers can learn about how the loss of the p53 gene leads to cancer. The image on the left shows tumor tissue. The red cells, which have lost p53, are cancerous, and the green cells are not cancerous. The image on the right is taken from normal tissue. It shows a few red cells that have the potential to become cancer interspersed among the green cells.
The vast majority of cancer genomic studies are based on analyzing human tumors, says Timour Baslan, the ONeil Charitable Trust Fellow in the Lowe Lab and one of the papers lead authors. The limited availability of patient tissue before and after tumor development means it has been impossible to gain a temporal picture of how p53 loss leads to cancer, starting from the earliest stages.
To bring those early changes into view, Drs. Baslan and Lowe along with former Lowe Lab members and cancer biologists Zhen Zhao and John P. Morris IV produced a unique mouse model of pancreatic cancer in which p53 mutational status can be detected, irrespective of tumor development, thereby allowing measurements of genetic changes as incipient cancer cells transition from a benign to malignant state.
The models key feature is a set of fluorescent tags that record specific genetic events and can be detected with a microscope. One tag is red and records the presence of a mutated KRAS gene known to be involved in promoting pancreatic cancer in both humans and mice. The other tag is green and records loss of p53. Cells with mutated KRAS but working p53 emit both red and green fluorescence, while cells that are missing p53 emit only red.
This visual trick allowed the scientists to identify specific populations of cells in the mouse that had lost p53 function but were still very far from being a full-fledged cancer. Its sort of like the first step when the wheels start to fall off the wagon, Dr. Lowe says.
By collecting these specific cells and then performing single-cell DNA sequencing on them, the scientists were able to identify the genetic changes that occurred immediately following p53 loss and continuing after.
The mouse really gave us the opportunity to look at a specific stage of cancer evolution, pull it out, and characterize it at a level thats has never been done before, Dr. Baslan says.
To the scientists surprise, the changes they observed always seemed to happen in a consistent pattern. First, the cells lost particular regions of chromosomes called deletions. Later on, genome doubling occurred, but only after a lot of deletions were accrued. Finally, following genome doubling, the cells continued to acquire further deletions but also uniquely gained additional copies of specific genes called gains and amplifications.
Since p53 mutations are often linked with genomic chaos, we were stunned to see there was a preferred order of events, says Dr. Morris, now an assistant professor at the University of North Carolina at Chapel Hill.
The mouse really gave us the opportunity to look at a specific stage of cancer evolution, pull it out, and characterize it at a level that's has never been done before.
Timour Baslan, research fellow
Even though cells from early stages had lost p53, the researchers were able to show that they were not yet cancerous, but instead, required these changes to look and act like cancer cells. Together, these observations suggested to the researchers that p53 loss by itself is not sufficient to cause cancer; instead, cells lacking p53 must acquire additional genetic changes, in an orderly manner, to fully go rogue.
Whats true of the mouse also seems to be true of humans: The scientists could see evidence that the same sorts of deletions, doublings, and amplifications that occur in the mouse also occur in human pancreas tumors.
And its likely not just pancreatic cancer that follows this pattern. Since the team has started discussing their results with colleagues at Memorial Sloan Kettering Cancer Center (MSK), others have been finding similar changes in cancer types besides pancreatic cancer.
Knowing that there are rules to the genetic evolution of tumors suggests a different way of thinking about treating them, the scientists say.
Many existing cancer drugs target gene amplifications in tumors. But because these are acquired late in tumor evolution, not all cells in the tumor will have them. This means that drugs targeting these amplifications may kill off only certain cancer cells, leaving others unscathed.
A more effective approach to treating cancer might be to target the gene deletions that occur very early in cancer development, since these changes will be found in all, or nearly all, tumor cells. (Changes that occur early in tumor evolution are called truncal changes because they are found in the trunk of the tumors evolutionary tree.)
Targeting these deletions could be tricky, but Dr. Lowe says the possibility is there: If its not genetic chaos, and theres order and rules to cancer development, then you might ultimately be able to exploit those rules against the cancer itself, he says.
Fittingly, this new paper comes just after the 30th anniversary of the publication of the original Nature paper, by scientist David Lane, that named p53 the guardian of the genome in the first place. Since that time, scientists have developed a much deeper understanding of p53s importance, with this latest paper bringing the multifaceted role of p53 into the sharpest focus yet.
Read the rest here:
SKI Scientists Solve 30-Year-Old Mystery About p53 Protein Dubbed Guardian of the Genome - On Cancer - Memorial Sloan Kettering
- The complete plastome sequences of invasive weed Parthenium hysterophorus: genome organization, evolutionary ... - Nature.com - February 18th, 2024 [February 18th, 2024]
- Multi-omic profiling reveals associations between the gut microbiome, host genome and transcriptome in patients with ... - Journal of Translational... - February 18th, 2024 [February 18th, 2024]
- Polymerase Chain Reaction (PCR) - National Human Genome Research Institute - February 18th, 2024 [February 18th, 2024]
- Genomic Time Machine Reveals Secrets of Human DNA - SciTechDaily - February 18th, 2024 [February 18th, 2024]
- 1 Million Unannotated Exons Discovered in the Human Genome - Technology Networks - February 18th, 2024 [February 18th, 2024]
- Hope for the night parrot: bird's full genome has been sequenced - Cosmos - February 18th, 2024 [February 18th, 2024]
- RevIT AAV Enhancer: Rev-up AAV genome production in upstream manufacturing - BioProcess Insider - February 18th, 2024 [February 18th, 2024]
- Multi-omics resources for the Australian southern stuttering frog (Mixophyes australis) reveal assorted antimicrobial ... - Nature.com - February 18th, 2024 [February 18th, 2024]
- Large-scale gene expression alterations introduced by structural variation drive morphotype diversification in Brassica ... - Nature.com - February 18th, 2024 [February 18th, 2024]
- Near-gapless and haplotype-resolved apple genomes provide insights into the genetic basis of rootstock-induced ... - Nature.com - February 18th, 2024 [February 18th, 2024]
- Secrets of Night Parrot unlocked after first genome sequenced - CSIRO - February 18th, 2024 [February 18th, 2024]
- CRISPR gene editing tool gets a revolutionary high-tech upgrade - Earth.com - February 18th, 2024 [February 18th, 2024]
- Ancient retroviruses played a key role in the evolution of vertebrate brains - EurekAlert - February 18th, 2024 [February 18th, 2024]
- Natural selection and genetic diversity maintenance in a parasitic wasp during continuous biological control application - Nature.com - February 18th, 2024 [February 18th, 2024]
- Hopes elusive parrots genome will provide answers - news.com.au - February 18th, 2024 [February 18th, 2024]
- MicroRNA is the master regulator of the genome researchers are learning how to treat disease by harnessing the ... - The Conversation - November 30th, 2023 [November 30th, 2023]
- "Ground-Breaking" Release of World's Largest Whole Genome Resource - Inside Precision Medicine - November 30th, 2023 [November 30th, 2023]
- Pangenome analysis reveals genomic variations associated with domestication traits in broomcorn millet - Nature.com - November 30th, 2023 [November 30th, 2023]
- Global genetic diversity, introgression, and evolutionary adaptation of indicine cattle revealed by whole genome ... - Nature.com - November 30th, 2023 [November 30th, 2023]
- Genome characteristics of atypical porcine pestivirus from abortion cases in Shandong Province, China - Virology Journal - Virology Journal - November 30th, 2023 [November 30th, 2023]
- Correcting modification-mediated errors in nanopore sequencing by nucleotide demodification and reference-based ... - Nature.com - November 30th, 2023 [November 30th, 2023]
- CRISPR-Based "Genome Shredding" Technique Shows Promise in Treating Glioblastoma - Inside Precision Medicine - November 30th, 2023 [November 30th, 2023]
- Genome wide analysis revealed conserved domains involved in the effector discrimination of bacterial type VI secretion ... - Nature.com - November 30th, 2023 [November 30th, 2023]
- TRISH to investigate the effects of spaceflight on the human genome, central nervous system - Odessa American - November 30th, 2023 [November 30th, 2023]
- The venom preceded the stinger: Genomic studies shed light on the origins of bee venom - EurekAlert - November 30th, 2023 [November 30th, 2023]
- Integrating genomic and multiomic data for Angelica sinensis provides insights into the evolution and biosynthesis of ... - Nature.com - November 30th, 2023 [November 30th, 2023]
- Genetic diversity and ancestry of the Khmuic-speaking ethnic groups ... - Nature.com - September 21st, 2023 [September 21st, 2023]
- Researchers to Apply Genome Analysis to Childhood Cancers; Goal ... - The Japan News - September 21st, 2023 [September 21st, 2023]
- How Bats' Genomes May Help Them Avoid Cancer and Survive ... - Technology Networks - September 21st, 2023 [September 21st, 2023]
- Longitudinal genomic surveillance of carriage and transmission of ... - Nature.com - September 21st, 2023 [September 21st, 2023]
- Whole genomes from bacteria collected at diagnostic units around ... - Nature.com - September 21st, 2023 [September 21st, 2023]
- Genome-wide identification of lncRNA & mRNA for T2DM | PGPM - Dove Medical Press - September 21st, 2023 [September 21st, 2023]
- Tasmanian tiger RNA is first to be recovered from an extinct animal - Nature.com - September 21st, 2023 [September 21st, 2023]
- Loneliness and depression: bidirectional mendelian randomization ... - Nature.com - September 21st, 2023 [September 21st, 2023]
- Rome Therapeutics adds $72 million to Series B round to harness ... - OutSourcing-Pharma.com - September 21st, 2023 [September 21st, 2023]
- Mystery of 'living fossil' tree frozen in time for 66 million years finally ... - Livescience.com - September 21st, 2023 [September 21st, 2023]
- Why the human genome could be healthcares holy grail - Yahoo Finance - May 4th, 2023 [May 4th, 2023]
- Scientists Compare Genomes of 240 Mammals to Understand Human DNA - The New York Times - May 4th, 2023 [May 4th, 2023]
- Genomes From 240 Mammalian Species Help Explain 100 Years Of Evolution And Human Disease - ABP Live - May 4th, 2023 [May 4th, 2023]
- 'Deletions' from the human genome may be what made us human - Yale News - May 4th, 2023 [May 4th, 2023]
- GeneDx Adds Buccal Swab as Non-Invasive Whole Genome ... - GlobeNewswire - May 4th, 2023 [May 4th, 2023]
- Whole-genome sequencing used to track down genes behind familial glioma - Medical Xpress - May 4th, 2023 [May 4th, 2023]
- Wiggly proteins guard the genome: Dynamic network in the pores of ... - Science Daily - May 4th, 2023 [May 4th, 2023]
- Genome-Wide Splicing Quantitative Expression Locus Analysis ... - Cancer Discovery - May 4th, 2023 [May 4th, 2023]
- Digital Genome Market is expand at a CAGR of 8.6% to reach USD ... - Digital Journal - May 4th, 2023 [May 4th, 2023]
- High School Students Learn the Basics of Base Editing to Cure GFP ... - University of California San Diego - May 4th, 2023 [May 4th, 2023]
- Genomic researchers gain access to CSIRO's AI-powered data ... - Microsoft - May 4th, 2023 [May 4th, 2023]
- Archaic hominin traits through the splicing lens - Nature.com - May 4th, 2023 [May 4th, 2023]
- Critical bug in genome sequencing device scores '10' on CVSS ratings - SC Media - May 4th, 2023 [May 4th, 2023]
- Novel Genomic Approach Ensures Better Diagnosis of Hereditary ... - Technology Networks - May 4th, 2023 [May 4th, 2023]
- Intellia Therapeutics: Leading the Way in Revolutionary Genome ... - Best Stocks - May 4th, 2023 [May 4th, 2023]
- Visual tracking of viral infection dynamics reveals the synergistic ... - Nature.com - May 4th, 2023 [May 4th, 2023]
- Genome | Genome LLC | United States - March 31st, 2023 [March 31st, 2023]
- Belarus: EU and WHO deliver equipment for research of genomes of infectious disease agents - EIN News - February 24th, 2023 [February 24th, 2023]
- Gene vs. genome: Definition, function, and impact - January 30th, 2023 [January 30th, 2023]
- Big cog in the wheel: As Covid worries reappear, Insacogs genome sequencing ability must be aided by govts - Times of India - December 25th, 2022 [December 25th, 2022]
- CapitalGainsReport Sector Spotlight: Healthcare Penny Stocks On The Move (ARDX, WHSI, BNGO) - Marketscreener.com - November 25th, 2022 [November 25th, 2022]
- Genome Insight and Kun-hee Lee Child Cancer & Rare Disease Project Team of SNUH (Seoul National University Hospital) Made an Agreement About a... - November 23rd, 2022 [November 23rd, 2022]
- Genome-wide association study reveals distinct genetic associations related to leaf hair density in two lineages of wheat-wild relative Aegilops... - October 19th, 2022 [October 19th, 2022]
- The Global Genomics Market to Exhibit Growth at a CAGR of 16.90% During the Forecast Period (20222027) | DelveInsight - Yahoo Finance - October 19th, 2022 [October 19th, 2022]
- Illumina and GenoScreen Partner to Expand Access to Genomic Testing for Multidrug-Resistant Tuberculosis - PR Newswire - October 19th, 2022 [October 19th, 2022]
- Superresolution Method Poised to Better Gene Function Understanding - Photonics.com - October 19th, 2022 [October 19th, 2022]
- Genome-centric analysis of short and long read metagenomes reveals uncharacterized microbiome diversity in Southeast Asians - Nature.com - October 15th, 2022 [October 15th, 2022]
- How a New Battery Data Genome Project Will Use Vast Amounts of Information to Build Better EVs - InsideClimate News - October 15th, 2022 [October 15th, 2022]
- Scientists Reconstruct the Genome of the 180-Million-Year-Old Common Ancestor of All Mammals - SciTechDaily - October 15th, 2022 [October 15th, 2022]
- Combining OSMAC, metabolomic and genomic methods for the production and annotation of halogenated azaphilones and ilicicolins in termite symbiotic... - October 15th, 2022 [October 15th, 2022]
- Concerted expansion and contraction of immune receptor gene repertoires in plant genomes - Nature.com - October 15th, 2022 [October 15th, 2022]
- Uncovering the Full Variant Continuum with Pioneering Solutions from Bionano - Inside Precision Medicine - October 15th, 2022 [October 15th, 2022]
- Metagenomic analysis of viromes in tissues of wild Qinghai vole from the eastern Tibetan Plateau | Scientific Reports - Nature.com - October 15th, 2022 [October 15th, 2022]
- Research Assistant in Molecular and Genome Editing Therapeutics job with KINGS COLLEGE LONDON | 311876 - Times Higher Education - October 15th, 2022 [October 15th, 2022]
- Lessons learnt from COVID-19 shed light on future pandemic preparedness - The Peter Doherty Institute for Infection and Immunity - October 15th, 2022 [October 15th, 2022]
- From Neanderthal genome to Nobel prize: meet geneticist Svante Pbo - Nature.com - October 8th, 2022 [October 8th, 2022]
- Revealing the genome organization of the earliest common ancestor of all mammals - Tech Explorist - October 8th, 2022 [October 8th, 2022]
- Mitochondrial DNA Is Working Its Way Into the Human Genome - Technology Networks - October 8th, 2022 [October 8th, 2022]
- Animated Map: Where to Find Water on Mars - Visual Capitalist - October 8th, 2022 [October 8th, 2022]
- Reconstruction of The First Mammal's Genome Suggests It Had 38 Chromosomes - ScienceAlert - October 6th, 2022 [October 6th, 2022]
- Genomic Science Breakthroughs Are Happening Faster Than Ever Thanks to HPC - CIO - October 6th, 2022 [October 6th, 2022]
- Genome Of Ancient Humans Is The Winning Field Of 2022's Nobel Prize in Medicine - IFLScience - October 6th, 2022 [October 6th, 2022]
- ASU professor to study new genome editing tools with NIH Innovator Award - ASU News Now - October 6th, 2022 [October 6th, 2022]
- New R&D norms to fast-track research on genome-edited crops - The Financial Express - October 6th, 2022 [October 6th, 2022]