[HN Gopher] Tiny DNA circles are key drivers of cancer, study finds
___________________________________________________________________
Tiny DNA circles are key drivers of cancer, study finds
Author : panabee
Score : 141 points
Date : 2023-04-15 15:39 UTC (7 hours ago)
(HTM) web link (med.stanford.edu)
(TXT) w3m dump (med.stanford.edu)
| Kalanos wrote:
| these need a more specific name because mitochondrial DNA is
| ecDNA and circular.
|
| i wonder if these are precursors to exosomes/vesicles
| [deleted]
| [deleted]
| mattwest wrote:
| The role of eccDNA in cancer is not a particularly new concept.
| However, studies like this are important to further elucidate
| cancer-promoting mechanisms.
|
| Additionally, the use of artificial eccDNA holds a lot of promise
| for genetic enhancement in many forms of life from humans, to
| livestock, to plants.
|
| Essentially, we could create artificial chromosomes which express
| useful genes or have inverted repeats which deliver siRNA to
| silence other genes and viruses.
|
| Similar to plasmids, except would have much larger payloads and
| ideally a heritable mechanism, perhaps by tethering against
| native chromosomes via zinc fingers, viral-encoded protein, or
| AT-hook motifs.
| jtbayly wrote:
| Reading this gives me an understanding for how some of my
| friends feel when I talk about technology.
|
| "Make sure to set the dip switches on your SCSI drive and
| confirm your cable is USB 4+ PD."
|
| Lol
| robocat wrote:
| Yeah, status seeking by using uncommon words or concepts,
| often noticeable in geek-culture. The same thing occurs in
| many cultures. "Well-educated" people in England might use
| more sophisticated[1] language and drop[2] references in
| Greek, Latin, or other languages of le tres bien formees.
| "Elucidate" feels like a status signal in the OP's comment.
|
| Personally one has been working on counter-signalling[3] by
| using simpler words and concepts, although one cannot say one
| is succeeding.
|
| [1] https://www.etymonline.com/word/sophisticated
|
| [2] fucked if I can find a good reference for my usage of
| "drop" here however hardly I tried
|
| [3] https://www.marketingsociety.com/the-library/counter-
| signall... - I chose this link because it appears to be well
| written and uses "elucidate"[0], "dropped" and "apercus".
|
| [0] They go on to elucidate. Apparently if you... play
| strategy s* = ( s*, s*M, s*) where s* < s*M. Let m describe
| beliefs that are Bayes consistent with playing s*. Then the
| expected gross payoff to sender q from signal s*M is
| Em[q'|s*M,q] = M ... Yup, they rather lost me at that point.
| woleium wrote:
| idk man, elucidate is pretty common if you spend a lot of
| time reading scientific papers (I'm assuming oop does).
| staunton wrote:
| Which only proves the point robocat was making
| robocat wrote:
| Exactly the point: well-educated people use words that
| appear in scientific papers. Showing you are well-
| educated is a common status signal amongst many well-
| educated people.
|
| Some people are lingual chameleons[1]: their language
| patterns completely change depending on their social
| surroundings. And many people are liguistic artistes[2]
| who choose their language to paint an image of
| themselves.
|
| However, failure is rife.
|
| [1] one Google result, different usage.
|
| [2] Sprachartisten
| matheusmoreira wrote:
| English Wikipedia is a surprisingly good resource.
|
| https://en.wikipedia.org/wiki/SiDNA
|
| So these things interfere with genetic operations in the
| cell, including cancerous cells. There's some evidence linked
| showing they enhance cancer treatments. Radiotherapy works by
| inducing cell and DNA damage in cancer cells, and these siDNA
| hurt their ability to repair themselves.
|
| https://en.wikipedia.org/wiki/Extrachromosomal_circular_DNA
|
| Circular strands of DNA that live outside the chromosome
| which are those X and Y things, a condensed form of DNA. Like
| a little DNA module floating about in the cell. What if you
| could develop new modules and deliver them to people's cells
| via viruses or something?
|
| Bacteria already have this capability - and more.
|
| https://en.wikipedia.org/wiki/Transformation_(genetics)
|
| Some of its friends died, releasing useful plasmids into the
| environment? They'll just absorb it. They're like the Mega
| Men of microbiology. Things die and they absorb their powers.
|
| https://en.wikipedia.org/wiki/Bacterial_conjugation
|
| Produce a literal pipe to transfer your antibiotic resistance
| super powers to your friend.
|
| Finally:
|
| https://en.wikipedia.org/wiki/Transduction_(genetics)
|
| Virus infects bacteria and adds its genetic material to it to
| make it produce copies. Those copies end up carrying some
| bacterial DNA in them though. This leads to some viruses
| turning into a DNA injection mechanism that transfer plasmids
| to other bacteria. Perhaps scientists will figure out how to
| use them to deliver DNA to our cells instead.
| chasil wrote:
| Regarding plasmids, there is a similar mechanism of DNA
| exchange in human cells known as "gypsy transposons," that
| are viral fragments which were partially integrated into
| germline ancestry.
|
| https://journals.plos.org/plosgenetics/article?id=10.1371/j
| o...
| matheusmoreira wrote:
| So retroviruses literally integrated into our biological
| processes and became physiological? That's seriously
| awesome.
|
| https://en.wikipedia.org/wiki/Retrotransposon
|
| > An endogenous retrovirus is a retrovirus without virus
| pathogenic effects that has been integrated into the host
| genome by inserting their inheritable genetic information
| into cells that can be passed onto the next generation
| like a retrotransposon.
|
| > When the retroviral DNA is integrated into the host
| genome they evolve into endogenous retroviruses that
| influence eukaryotic genomes.
| chasil wrote:
| I read recently that DNA transcription for protein
| expression is able to identify and skip an inserted
| element, but that the protein will be slightly different
| at the boundaries.
|
| It appears to have gone badly wrong for the "Tasmanian
| Devil."
|
| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4802805/
|
| https://www.science.org/content/article/origin-tasmanian-
| dev...
| robwwilliams wrote:
| You are right. In the same issue there is also a paper from
| Andreas Beyer's team on the effects of aging on faster error-
| prone transcription in several species.
|
| Age-related difference (interpreted naturally as transcription
| errors) cut out the wrong pieces of precursor mRNAs and this
| can lead to RNAs and circular RNAs in the cytoplasm. Not to
| mention strange mRNA isoforms. Probably not a good thing.
|
| K. Mozhui and others have shown an increase is epigenetic noise
| with age in mice and there is similar work in "wild" human
| cohorts.
|
| But the key questions in all of this work are---What is causal?
| What is just consequence?
|
| The multiple flows of causality is a very tricky problem.
| Genetic variants are the most obvious candidates once
| environmental factors (radiation exposure, toxins, diet) are
| reduced or standardized in a well controlled laboratory
| environment.
| chasil wrote:
| Is this ecDNA of similar size to the circular DNA of the
| mitochondria?
|
| This seems like a reversion of the form of DNA to a prokaryotic
| state.
| robwwilliams wrote:
| Highly variable. In cancers they can be much larger.
| Mitochondrial circular DNA is about 16,600 basepairs. In
| comparison, in the paper below one example of a cancer-driven
| ecDNA is 1,260,000 basepairs (EGFRvIII). ecDNA were
| originally detected using cytogenetic light microscopic
| methods, hence the original bias toward large size.
|
| Wikipedia article:
| https://en.wikipedia.org/wiki/Extrachromosomal_DNA
|
| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5334176/
| anonymouskimmer wrote:
| It ranges from much smaller to much larger than mitochondrial
| genomes.
|
| https://en.wikipedia.org/wiki/Extrachromosomal_circular_DNA
|
| > Extrachromosomal circular DNA is derived from chromosomal
| DNA, can range in size from 50 base pairs to several mega-
| base pairs in length, and can encode regulatory elements and
| full-length genes. eccDNA has been observed in various
| eukaryotic species[2][3][4][5][6][7][8] and it is proposed to
| be a byproduct of programmed DNA recombination events, such
| as V(D)J recombination.
|
| There are basically two ways to keep DNA from degrading in
| the cell: protect the ends with special proteins or DNA
| structures, or make it so that there are no ends to protect
| by having the DNA be circular.
|
| https://en.wikipedia.org/wiki/Linear_chromosome
|
| > Linear chromosomes are not limited to eukaryotic organisms;
| some prokaryotic organisms have linear chromosomes as well.
|
| > a good number of eukaryotic species do harbor linear mtDNA
| <mitochondrial DNA>, some even broken into multiple molecules
| anonymouskimmer wrote:
| Cre-lox recombination is effectively payload-unlimited. Why
| create an artificial chromosome when inheritance is intended
| when you can just add to a current chromosome?
|
| > perhaps by tethering against native chromosomes via zinc
| fingers, viral-encoded protein, or AT-hook motifs.
|
| It sounds complex. Partition loci would be sufficient for
| inheritance in both offspring cells.
| mbreese wrote:
| But they can also be devious.
|
| Because they aren't under the same selective pressure as normal
| chromosomes, the number of ecDNA molecules can be highly
| variable between daughter cells. This is one of the potential
| resistance mechanisms for a tumor. If you have a drug that
| targets a gene in the ecDNA, the tumor could only keep clones
| with a small number of ecDNAs during treatment. Then after the
| drug has cleared, the number of ecDNAs can then rise again.
|
| When you lose the default 2 copy state, natural selection can
| follow non-Mendelian patterns.
| gardenfelder wrote:
| Open Access:
|
| https://www.nature.com/articles/s41586-023-05937-5
| saranormous wrote:
| is there good background reading on ecDNA somewhere?
| panabee wrote:
| if you are a cancer researcher, please share research assumptions
| that are debunked yet still commonly held.
|
| i'm compiling a list.
|
| these must be empirically supported.
|
| for instance, i believe negative conclusions based on knockout
| studies are misleading, but this is not empirically proven and
| would not qualify. (if you knock out a fire alarm and the house
| still functions, saying the alarm serves no purpose is flawed.)
| ly3xqhl8g9 wrote:
| Levin, M. (2021), "Bioelectric Signaling: Reprogrammable
| Circuits Underlying Embryogenesis, Regeneration, and Cancer",
| _Cell_ [1] is a general overview how cancer is a breakdown in
| communications leading to a down-scale of the self for the
| affected cell, see also Levin, M. (2021), "Bioelectrical
| approaches to cancer as a problem of the scaling of the
| cellular self", _Progress in Biophysics and Molecular Biology_
| [2]; for more articles [3].
|
| In video format: "Why don't (today's) Robots get Cancer" [4]
|
| [1]
| https://www.cell.com/action/showPdf?pii=S0092-8674%2821%2900...
|
| [2]
| https://www.sciencedirect.com/science/article/abs/pii/S00796...
|
| [3] https://drmichaellevin.org/publications
|
| [4] https://www.youtube.com/watch?v=L43-XE1uwWc
| dkural wrote:
| A knock-out study will work as well as the precise definition
| and measurement of the phenotype you're looking for will allow.
| The point you're making is well understood by geneticist.
| There's about 22K genes in the genome, if your typical genetic
| screen returns a list of a 0 to 1K positives, no one is
| claiming that the 21K genes are absolutely uninvolved in the
| phenotype.
| panabee wrote:
| i have read many studies that claimed a gene had no function
| in a pathway after performing knockout and observing no
| effect.
|
| there are many great research papers, but there are also many
| flawed ones.
___________________________________________________________________
(page generated 2023-04-15 23:01 UTC)