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Old 05-17-2012
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DNA Replicative error phenotype and HNPCC

Does anyone know what is replicative error phenotype and what is its relationship with the HNPCC?

Thanks
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Old 05-17-2012
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i am not sure if i get ur question right but

a mutation in one of these 2 genes;hMSH2 & hMLH1 initiates defective repair of DNA mismatches resulting to HNRCC(lynch syndrome)

hope this helps
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Old 05-17-2012
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Quote:
Originally Posted by imgchuchu View Post
i am not sure if i get ur question right but

a mutation in one of these 2 genes;hMSH2 & hMLH1 initiates defective repair of DNA mismatches resulting to HNRCC(lynch syndrome)

hope this helps
Hey imgchuchu,

In Dr. Najeeb's video (part 8 of neoplasm series), he talked about microsatellite instability, replicative error phenotype and their relationship with the HNPCC but I had troubles understanding what he was talking about...and I am not sure if replicative error phenotype has something to do with microsatellite instability
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Old 05-17-2012
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If you have a mutation in the tumor suppressor genes MLH-1 or MSH-2. You'll have increased errors in DNA mismatch repair that occurs after replication (G2 phase). Due to this you'll find increased microsatellite instability in these patients, and they're also usually the ones that present with HNPCC.

So there is a correlation b/w increased microsatellite and HNPCC, because both are due to errors in DNA mismatch repair.
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Old 05-18-2012
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Quote:
Originally Posted by slowpoke View Post
If you have a mutation in the tumor suppressor genes MLH-1 or MSH-2. You'll have increased errors in DNA mismatch repair that occurs after replication (G2 phase). Due to this you'll find increased microsatellite instability in these patients, and they're also usually the ones that present with HNPCC.

So there is a correlation b/w increased microsatellite and HNPCC, because both are due to errors in DNA mismatch repair.
How does the mutation in the DNA mismatch repair gene leads to microsatellite instability (since in microsatellite instability, there is a lengthening/shortening of the repeats)?
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Old 05-19-2012
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Sorry for the late reply. From what I remember, microsatellite instability is due to errors made by DNA polymerase during replication (the S phase). What happens is the DNA polymerase as it copies the repeats either adds too much of the repeated nucleotides or doesn't add enough, so this results in a few nucelotides that were synthesized that doesn't base pair with the parental/template strand. It's the job of mismatch repair enzymes to splice these out and 'fix' the mismatched segment. But since this doesn't happen when the mismatch repair enzymes are mutated, you have a few nucleotides in the new replicated DNA strand that are not paired and stick out.

When the cell divides and replication happens in the cell that 'inherited' the mismatched sequences, the abnormal number of repeats in the segment is conserved. As this cell goes into the S-phase the parental DNA strand separates and the expanded or contracted repeat sequence acts as a template for replication, the DNA polymerase will simply replicate this altered strand faithfully. So when this cell divides, you'll have a new daughter cell that has an expanded/contracted number of repeats in both strands. This difference in the length of the repeated sequence between the new cell, and the normal cells is what's called microsatellite instability.

Hope that helps. Ohh yeah, If I'm wrong, hopefully someone corrects me, Thanks
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Last edited by slowpoke; 05-19-2012 at 12:41 PM.
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Old 05-20-2012
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Quote:
Originally Posted by slowpoke View Post
Sorry for the late reply. From what I remember, microsatellite instability is due to errors made by DNA polymerase during replication (the S phase). What happens is the DNA polymerase as it copies the repeats either adds too much of the repeated nucleotides or doesn't add enough, so this results in a few nucelotides that were synthesized that doesn't base pair with the parental/template strand. It's the job of mismatch repair enzymes to splice these out and 'fix' the mismatched segment. But since this doesn't happen when the mismatch repair enzymes are mutated, you have a few nucleotides in the new replicated DNA strand that are not paired and stick out.

When the cell divides and replication happens in the cell that 'inherited' the mismatched sequences, the abnormal number of repeats in the segment is conserved. As this cell goes into the S-phase the parental DNA strand separates and the expanded or contracted repeat sequence acts as a template for replication, the DNA polymerase will simply replicate this altered strand faithfully. So when this cell divides, you'll have a new daughter cell that has an expanded/contracted number of repeats in both strands. This difference in the length of the repeated sequence between the new cell, and the normal cells is what's called microsatellite instability.

Hope that helps. Ohh yeah, If I'm wrong, hopefully someone corrects me, Thanks
Read two of your posts (the other one was the explanation you gave for viral load test for HIV) and I can see that you have very clear concepts. I'm interested to know how you're studying, which question banks you're using, etc. Thanks.
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Old 05-21-2012
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Quote:
Originally Posted by slowpoke View Post
Sorry for the late reply. From what I remember, microsatellite instability is due to errors made by DNA polymerase during replication (the S phase). What happens is the DNA polymerase as it copies the repeats either adds too much of the repeated nucleotides or doesn't add enough, so this results in a few nucelotides that were synthesized that doesn't base pair with the parental/template strand. It's the job of mismatch repair enzymes to splice these out and 'fix' the mismatched segment. But since this doesn't happen when the mismatch repair enzymes are mutated, you have a few nucleotides in the new replicated DNA strand that are not paired and stick out.

When the cell divides and replication happens in the cell that 'inherited' the mismatched sequences, the abnormal number of repeats in the segment is conserved. As this cell goes into the S-phase the parental DNA strand separates and the expanded or contracted repeat sequence acts as a template for replication, the DNA polymerase will simply replicate this altered strand faithfully. So when this cell divides, you'll have a new daughter cell that has an expanded/contracted number of repeats in both strands. This difference in the length of the repeated sequence between the new cell, and the normal cells is what's called microsatellite instability.

Hope that helps. Ohh yeah, If I'm wrong, hopefully someone corrects me, Thanks
Hey slowpoke,

Thanks for the explanation.

But I am having trouble understanding how the DNA polymerase either "adds too much of the repeated nucleotides or doesn't add enough", is this some sort of an addition/deletion mutation in the newly synthesized strand? I thought it's more probable for the DNA polymerase to undergoes mismatch rather than addition/deletion of the replicated sequence.

Your help will be greatly appreciated
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