"This" is called SIRT6 and it plays a major role in DNA repair, especially Non-Homologous End Joining. (NHEJ). The graphic below depicts a double strand break (DSB) in DNA (top) undergoing repair by the NHEJ process. The next images, below the top one, depict how different proteins are recruited to effect the DSB repair. It doesn't include SIRT6 because the graphic is old.
Ionizing radiation produces about 5-7% as many DSB's as Single Strand Breaks (SSB's), and DSB's and SSB's also occur metabolically. Even when a DSB is repaired, typically some nucleotides (DNA's basic units abbreviated A,T, C and G) are gained or lost at the repair sites. Occasionally, there can be large sections of DNA deletions. So, DSB repair is usually actually misrepaired.
With that FACT (DNA repair has fidelity <100%) we conclude there is >0% DNA damage risk associated with ionizing radiation exposure. And as far as we know today, cancer is a result of accumulated DNA damage.
The new study informs us that as cells age (at least in mice), they undergo more NHEJ and lose SIRT6.
Of course, we know what some HP deniers will do........
"and DSB's and SSB's also occur metabolically"
ReplyDeleteand therefore the logical question is how many DSB's and SSB's occur "metabolically" per cell per hour? Compared with the number caused per cell per hour by low radiation level exposures? Is one is a couple of orders of magnitude bigger than the other?
I don't see what difference it makes. If the metabolically generated damage gives you a cancer risk of X, then the radiation generated damage adds Y to the X. Does it really matter if X is 1000, and Y is 1? Or if they are both 5? That just relates the risk per dose of radiation using a narrow metric. DSB's and SSB's are not the only types of damage. See the video within the post DNA Damage & Repair.
ReplyDeleteA better metric is human epidemiology of cancer comparing excess risk of cancer from radiation, with a background risk (which includes metabolic risk, other chemical exposures, sunlight, etc. and includes all forms of DNA damage and repair). In the U.S. the background risk of cancer incidence is 42% and a dose of 0.1 Sv adds a 1% excess risk.
That moves the goalposts a little... but given what you write, I guess then the logical question is: why is the Denver background risk of cancer lower than the overall background risk in the US if the background radiation rate is higher in Denver?
ReplyDeleteI didn't move the goalposts, there isn't much point in comparing the rates of DSB's/SSB's from metabolism and radiation. Most of the metabolic damage occurs in the mitochondria, the radiation damage can occur throughout the cell, though we're mostly concerned with the nucleus. There isn't a way to scale any differences up to anything meaningful at the human (rather than cell) level. The point is, that damage plus damage is greater damage.
ReplyDeleteDo you think that background radiation is the only contributor to cancer?
Also, I meant to add that if one looks at averages, one commits the ecologic fallacy (search the term). We need to look at individuals and at the actual dose the individual receives, not broad averages.
ReplyDeleteObviously, bkgd. radiation isn't the only contributor to cancer. There are lots of contributors, picking only one is the cherry-picking fallacy (search the term).
Well, I was originally referring to the cellular damage... which was the subject of the article... then you brought in the whole body, asking why did it matter what went on per cell. Now since there are at least 10**13 cells in my body (10 trillion - I have a small body and brain), if as you say in the article "DSB repair is USUALLY actually misrepaired", I would logically want to know how many there are of these and work out why I am still alive and kicking without as yet a preponderance of "accumulated DNA damage" after one hour of life... do my repair mechanisms work better than USUALLY (since, in case you did not know, each of my cells "naturally" by whatever cause suffers many DSB's and SSB's per hour)?
ReplyDeleteYes, I understand that you were originally referring to the cellular damage, and thank you for comment(s). But it seems to me to originally ask what the comparison is between metabolic damage and radiation damage, is different than asking how is the body able to cope with this damage, which seems to be what you are now asking.
ReplyDeleteThe differences in damage rates (your original question) don't matter for the reasons I gave. Radiation damage is added to metabolic damage. The damage occurs in different places and the nature of the DSB's is different (I haven't described those differences, and I may do a separate post on them). The outcome of concern with accumulated DNA damage is cancer, that's why I shifted to the whole body. We need to look at all contributions to cancer across the body, and not focus on one or two cellular phenomena.
There are certainly individual differences in terms of susceptibility to DNA damage. Some people are born with mutations which make them more susceptible to cancer. But generally, cancer is a disease of aging, because of the accumulation of DNA damage over time. Cells can incur some damage, and then just die to be replaced with new cells. The cells don't incur enough damage over their lives to cause cancer. If the DNA damage occurs within "junk" DNA, the damage is of no consequence. The damage may signal a cell to undergo programmed suicide or apoptosis, so the damage doesn't play out within the body. Or the consequences of the damage can be minor, like a slight increase or decrease in the production of a protein, which doesn't cause any major problems. Some cells on their way to cancer appear as foreign bodies to the immune system, and it kills them before they metastasize.
You might want to watch the video embedded within my post "DNA Damage & Repair" which you can find along the right hand side.