Colon cancer-associated mutator DNA polymerase δ variant causes expansion of dNTP pools increasing its own infidelity Flashcards
Which DNA polymerases are implicated in hereditary colorectal cancer?
DNA polymerases delta and episilon.
How does polys-r696W become so mutagenic?
causes s-phase checkpoint-dependent expansion of dNTP pools. Results from errors in nucleotide selectivity defect with activation of the signaling pathway that elevates dNTP pools.
DNA polymerase delta
pol3; Lagging strand synthesis
DNA polymerase epsilon
pol2; Leading strand polymerase.
Who introduced the concept of a mutator phenotype leading to cancer?
Lawrence Loeb
Dun1 effector Kinase
plays a role in the regulation of dNTP pools and the transcriptional response to DNA damage.
What enzyme precisely regulates dNTP pools during the cell cycle?
Ribonucleotide reductase (RNR)
What causes higher levels of dNTP pools?
When cell damage occurs, Mec1, Rad53, and Dun1 levels increase causing higher levels of RNR activity.
Why is an increased amount of dNTPs harmful?
pool expansion following DNA damage is accompanied by increased error rate. Leads to mutagensis.
How exactly do polymerase 2/3 lead to mutagenesis?
pol2 or 3 mutant and Dun1 interact to increase dNTP levels
sm1 and crt1
repressors of RNR
Which polymerase is more error prone?
pol3 R696W
Poly3-R696W hypothesis
Pol3-R696W is incapable of correcting polyd-R696W errors by the proofreading activity of pold and or MMR. It is found that when poly3-R696w interacts with genes that also have mutations (MMR or other repair mechanisms), mutation rates are synergistic.
