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Lecture 5

Cell Biology - Lecture 5 - Video 2.1 - Notes

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CAS BI 203
Martin Steffen

Lesson 5 – Video 2a [00:00:00.00] 1903 [00:00:01.48] SPEAKER 1: In these next few videos, we'll talk about DNArepair-- what 1904 happens when DNAis damaged from external environmental conditions or when a mistake is 1905 made during replication. Mistakes or damage is often referred to as mutations. These can have 1906 deleterious effects causing various diseases. 1907 [00:00:25.58] We'll take a look at the amount of DNAdamage that occurs each day. And it's 1908 pretty staggering.And then, in the second video, we'll talk about three different ways of 1909 repairing three different types of DNAlesions. 1910 [00:00:43.70] But first, we'll go with some background. So here, you have a piece of double 1911 stranded DNA. And a mistake has been made. The original DNAhad a G.And there should have 1912 been a C over here. But instead, anAhas been inserted. 1913 [00:01:02.23] Now, when it comes time for DNAsynthesis, and these two strands separate, and 1914 both are used as templates for the next generation of cells, this A, if properly replicated, will be a 1915 template for T. This G will be a template for the proper insertion of a C nucleotide, which is 1916 what it should have been here. 53 [00:01:28.18] And so that 50%, in this case, of the daughter cells 1917 will be mutated at this position. 1918 And 50% of the cells will be correct. This is in the absence of any kind of DNArepair. And we'll 1919 explore the consequences of this in a few slides. 1920 [00:01:51.89] As mentioned, not only can there be mistakes made during synthesis, but there can 1921 be lots of damage done to a cell. This is an amazing table, which I just saw recently in a talk by 1922 Yosef Shiloh who did some work examining and quantitating the amount of damage done to a 1923 single mammalian cell, so to 3 billion base pairs in a single day. 1924 [00:02:16.37] And I have to say, I found the numbers to be staggering. I had no idea they would 1925 be this large. However, the cells are going to, on average, repair every single one of these 1926 mistakes. So our DNArepair machinery is phenomenal in its capabilities. 1927 [00:02:40.31] I'd like to demonstrate the consequences of mutation with the first molecularly1928 defined disease.And that is sickle cell disease, sickle cell anemia. It was identified that in 1961, 1929 sickle cell occurred because of a single nucleotide change of anAto a T.And this has the 1930 consequence of replacing a hydrophilic amino acid, glutamic acid, on the surface of a protein to a 1931 hydrophobic amino acid, valine. 1932 [00:03:13.62] And we'll discuss in class how this single amino acid mutation causes this sickling 1933 effect that you see on the right here of these red blood cells. This is their normal shape. This is 1934 the sickled shape. You already have enough information based on the lectures of protein 1935 structure to figure that out. But let's discuss that. 1936 [00:03:37.47] I also feel compelled to point out that it's been over 50 years since we identified 1937 the mutation responsible for the disease. Yet, we do not have significantly improved treatments 1938 for the disease. Your prognosis is not that different if you get diagnosed today with sickle cell 1939 disease as compared to when you would get diagnosed back then. There's greater support of 1940 medical care, but not treatments that attack the underlying disease. 1941 [00:04:05.00] The point I'm making is that you'll hear all the time in the popular literature, oh, a 1942 big breakthrough-- we found the gene for this disease. But that still can be an incredibly long 1943 way to go before you actually make patients better once you know the disease gene. And you 1944 might also ask, why have there been no improvements?And I would say the short answer is, 1945 developing effective new treatments for disease is really, really hard. 1946 [00:04:40.67] One of the ways to avoid having to correct a lot of mistakes or mutations is to not 1947 make mistakes in the first place.And the DNApolymerase does this by using several different 1948 mechanisms. Here on the top, we see a template strand and a growing strand.And as you can 1949 see, an error has been made. Somehow, a C was incorporated where there should have been a T 1950 base. 1951 [00:05:10.56] This is already a rare event. But it does happen. Now the polymerase is coming in 1952 and trying to add a second base. But it's going to recognize that the base which its trying to 1953 attach the new base to the 3' hydroxyl is not correctly binding the existing template strand.And 1954 so that will cause it to recognize not to make an attachment here. 54 [00:05:37.58] And instead, what it can do is it has a 3' to 5' exonuclease 1955 activity. That means 1956 starting
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