DNA Replication Editing and Telomeres part 7

DNA polymerase has an editing function to reduce mutations, but mutations still occur spontaneously with every replication.
Mutations are base changes (e.g., A to C). The cell tries to correct these mutations using the template strand.
During replication, the parental strand serves as the template to correct the newly made strand.
Enzymes repair DNA and correct spontaneous mutations.
DNA polymerase can correct errors during replication.
Sequence changes can become permanent and be passed to the next generation if they occur in cells undergoing meiosis.
Mutations can be deleterious, neutral, or beneficial, providing variation for natural selection.
Random DNA mutations passed on to offspring can lead to a survival advantage in changing environments.

DNA polymerase can add nucleotides to a primer or an elongating strand.
Elongation occurs at the 3' OH end.
If there is an A on the template strand, T should be added, but sometimes C is mistakenly added, causing incorrect base pairing.
DNA polymerase uses a "backspace" function to remove incorrectly paired nucleotides.
The polymerase prefers a correctly base-paired 3' end to continue adding nucleotides.
Example: If the template strand has a series of A's, T's should be added. If the wrong base is added, the polymerase removes it.
Exonuclease function: ability to remove the last nucleotide added
This ensures the correct nucleotide is added according to base pairing rules (G with C, T with A).

Sometimes, DNA polymerase misses an incorrect base, and it gets incorporated.
Other repair enzymes recognize bulges or structural differences in the DNA and correct the error.
UV radiation can cause thymine dimers, which are covalent bonds between adjacent thymine nucleotides, causing a bulge.
Nucleotide excision repair: enzymes cut out the damaged nucleotides, use the template to fill in the gap, and seal the sugar-phosphate backbone.
This fixes damaged stretches or improperly base-paired nucleotides that were not fixed by DNA polymerase or occurred spontaneously.
Nucleotides can spontaneously change, such as by deamination (loss of an amino group), which changes the base.
Enzymes recognize and fix these changes.
Analogy: Like correcting errors in a textbook where the cat has changed letters with its ink-covered paws.
DNA polymerase are not fully error free.

DNA polymerases require a base-paired 3' OH to add nucleotides and cannot start a new strand from scratch.
The need for primers creates a problem at the ends of linear chromosomes.
The usual replication machinery does not complete the 5' ends, leading to shorter DNA molecules with each replication.

Two DNA strands are separated for replication.
Leading strand synthesis: a primer is added, and synthesis occurs in the 5' to 3' direction continuously.
Lagging strand synthesis: primers are added as the region opens up, and backstitching is required.
Primers are removed, which creates a problem at the ends.

Telomeres are unique sequences at the ends of linear chromosomes, distinct from centromeres.
They consist of repeat sequences of six nucleotides repeated thousands of times.
Telomeres protect genes near the ends of chromosomes and act as a protective cap.
Without telomeres, chromosomes would shorten with each division, which is linked to cellular aging.
Shortening telomeres can act as a clock, indicating how old the cell is and how many times it has divided.
This mechanism is protective against cancer because cancer cells ignore these signals and divide uncontrollably.
Cells with shortened telomeres undergo replicative senescence and stop dividing.
This prevents cells with accumulated mutations from continuing to divide.
Telomeres are like the plastic aglet on the end of a shoelace, protecting the ends of the chromosome.
Telomere shortening may protect cells from cancerous growth.

On the lagging strand, after primer removal, there is no 3' end to add to at the end of the chromosome.
This leads to chromosome shortening because the information at the very end cannot be copied.

Telomerase is an enzyme that extends the 3' end of chromosomes to maintain chromosomal length, particularly in stem cells.
Telomerase uses an RNA template to add repeat sequences to the 3' end.
The telomeric sequence in humans is GGGTTT.

Telomerase extends the 3' end by adding nucleotides according to the RNA template.
The telomerase enzyme, with its RNA template, slides and catalyzes the addition of the same six nucleotides repeatedly.
This lengthens the telomeric sequence.

Extending the 3' end allows a primer to be placed further out.
After the primer is laid down, DNA polymerase can fill in the gap.
The RNA primer is then removed, but this is not a problem because the 3' end has been extended.
Without telomerase, a region would not be copied in the new strand.
High telomerase expression prevents chromosome shortening.
Reducing telomerase expression causes cells to age and stop dividing.
Telomeres protect chromosome ends, allowing the long piece to fold back and tuck in.
Proteins, like shelterin, bind to the folded end, creating a protective cap and preventing the cell from recognizing it as a double-stranded break.

Stem cells maintain high telomerase expression to maintain their ability to divide.
Somatic cells reduce telomerase expression and age by tracking the length of their chromosomes.