Our world can be described at many fundamental levels. The way I look at it, Math describes Physics, which describes Chemistry, that dictates Biology, and everything is just downstream from there! So you want to know bio? You need to know chemistry. A basic chemical principle underlies why some genes are transcribed more frequently than others, Methylation (adding methly) and acetylation (adding acetyl) patterns of histones. All you need to know about histones for now is that they're small little proteins that DNA wraps around allowing them to pack into a small discrete area. When the DNA is bound tightly to the histone, there's not enough room for transcription, and when it's loose, the molecular machines can come in and do their work. So what chemical principle underlies "tight" or "loose" binding and subsequently transcriptional control?
It has the do with charge, polarity, and electronegativity! Super basic chemistry when you really think about it. Some background you need to have: The surface of a histone has a + charge The phosphate backbone of DNA gives it a - charge So naturally, the DNA is tightly bound to histone and as discussed that doesn't leave for the molecular machines to come in and do their job. Methyl = adding a CH3 groups Acetylation = adding a C=OCH3 group Electronegativity is a measure of the tendency of an atom to attract a bonding pair of electrons. In terms of electronegativity: C = H < N < O where Carbon is the weakest attractor of electrons and Oxygen is the strongest attractor So, when we add a methyl group to a histone, the nitrogen tends to suck away electrons from the methyl group giving itself a GREATER - charge. More - charge = tighter DNA binding When we add an acetyl group the oxygen pulls electrons away from the nitrogen giving the histone a LOWER - charge are thus decreasing the electrostatic attraction between DNA and histone. That's all there is to it!
Why can some people smoke cigarettes their entire lives and die old and "healthy" avoiding cancer and the multitude of maladies associated? And what is molecular correlate to this boggling phenomenon?
When we look at cancer, we need to think of it more as a genetic lottery. When you hit the lottery, you develop cancer. Some people are born with more lottery tickets than others which we can't control in our day to day lives. Every day you expose yourself to some environmental "insult" such as air pollution, undue UV radiation, drugs, poor diet, etc, you buy another ticket!! So now what does a "ticket" look like the molecular level? Well, there's plenty of routes to take here, but a rather simple one to understand is the telomere. Don't forget the central dogma of biology, DNA --> RNA --> Protein. Proteins regulate every function in our body to a degree, but let us trace it back to the source, damage to DNA resulting in faulty protein. So now there are parts to understand. 1: Why do we need telomeres. 2: How do insults influence telomeres? 3) How do insults, telomeres, DNA damage, and cancer tie in together? 1) Whenever a gene is transcribed (made into RNA) a little molecular machine needs to physically bind to the gene and then spits out the appropriate RNA code to be shipped out and made to protein. What needs to be considered is that the site where this machine binds cannot be transcribed, it can only transcribe what's ahead of it in on track. So this molecular machine needs to bind to what we call a telomere which is a stretch of code not needed in the RNA and resultant Protein sequence and thus is cleaved off at the end of transcription, getting smaller and smaller you need to transcribe the protein. 2) Cells are in a constant state of "turnover" in that they're being replaced by fresh ones all the time on an as needs basis. Thus, telomeres are constantly being shorted (which also suggests that humans may have a natural countdown to death but that's another topic) by normal cell processes, so what happens if you speed this up? Every Time you introduce another "insult," you damage a cell and call upon gene transcription to replace the cell and all the associated parts. So the more frequently you add "insult" you are shortening the telomeres at a faster than normal rate and cells are turning over more rapidly than usual. 3) Now to tie it all together! When you run out of telomeres, and you call on a gene to be transcribed, you can't make the right RNA and thus the right protein. As you may recall, the part that the molecular machine binds to has to get cleaved off along with the machine and whatever is left over eventually codes for the protein. Now without telomeres, you're making the wrong/broken proteins!!! Faults in gene transcription and shortened telomeres to date have been implicated in pancreatic, bone, prostate, bladder, lung, kidney, and head and neck cancer. We're even verging on the role of telomeres in again. So why should you wear sunscreen, avoid cigarette smoke, eat a healthy diet, and make sure you get fresh air? To keep those telomeres nice and long!
The adage goes "form follows function" meaning that the function of a protein (or polypeptide) is contingent on it's 3 dimensional shape. We know that polypeptide's are made from a base of 20 amino acids, thus the possible combinations of a given polypeptide are x^20 where x is number of amino acids in a polypeptide. That quickly reaches astronomical proportions, and then when we look at the possible combinations of how it can fold, Levinthal's paradox shows up that we're reaching time frames greater than the entire age of the universe! So how do we get a definite 3D shape from a nearly infinite combination of 1D arrangements?
3D shape must be encoded into the 1D primary sequence of a protein! Just following the math, we know that a protein can't simply be trying every possible combination of folding until it finds the "correct" one. Something about how those initial amino acids were chosen tells the protein what direction to start folding in. As this question was posited more models emerged and that way we look at protein folding now is more of an "energy funnel." As everything in the universe it still follows the law of thermodynamics! As the protein "attempts" a given configuration it gets "feedback" and "knows" if the attempted configuration has higher or lower free energy. As the laws of thermo tell us, for a given reaction to proceed spontaneously, it must have a negative change in free energy. Rather than attempt every possible configuration of folding, the protein has to feel out the energy terrain and gets a better idea of if it's going the "right" or "wrong" way. Check out this picture: http://cbc.arizona.edu/classes/bioc462/462a/NOTES/Protein_Structure/Fig6_29FrEnergyFunnelFold.GIF