Risks at the DNA Replication Fork: Effects upon Carcinogenesis and Tumor Heterogeneity
Abstract
:1. Introduction
1.1. An Overview of the Eukaryotic DNA Replication Fork
1.2. Mismatch Repair Deficiencies Promote Cancer
1.3. Mutagenic Human Replicative Polymerase Variants Give Rise to Cancer
1.4. Damage to Single-Stranded DNA on the Lagging Strand Template Causes Mutation in Cancer
1.5. Future Directions: Tumor Specific Metabolic Changes as Modulators of Replication Fork-Associated Mutagenesis
2. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Amino Acid Change 1 | Somatic/Germline | Cancer Type 2 (n) 3 | Mutator Phenotype in Yeast [References] | Biochemical Support/Enzyme [References] |
---|---|---|---|---|
POLD1- | ||||
D316G | Germline [86] | CRC, EC, and breast | Yes [87] | Yes/T4 polymerase [88] |
D316H | Germline [86] | CRC and breast | Yes [87] | Yes/T4 polymerase [88] |
P327L | Germline [83] | None, patient had multiple colonic adenomas | Yes 5 [89] | Yes/human Polε [45] |
R409W | Germline [86] | CRC | N.d. | N.d. |
L474P | Germline [86] | CRC and EC | Yes [87] | Yes/human Polε [45] |
S478N | Germline [83] | CRC and EC | Yes [83] | N.d. |
POLE- | ||||
W347C | Germline [85] | Cutaneous melanoma | Yes [85] | N.d. |
N363K | Germline [90] | CRC and EC | N.d. | N.d. |
D368V | Germline [91] | CRC | N.d. | Yes/T4 polymerase [88] |
P436S | Germline [92] | CRC | N.d. | N.d. |
Y458F | Germline [93] | CRC | N.d. | Yes/T4 polymerase [88] |
L424V/I | Both [83] | Hereditary CRC, EC (2) 4, breast (1) 4 | Yes 6 [87] | Yes/human Polε [45] |
P286R/L/H | Somatic | CRC (5), EC (10), breast (1), stomach (1), pancreas (1) | Yes [89] | Yes/human Polε [45] |
F367S | Somatic | CRC (1) | N.d. | Yes/human Polε [45] |
V411L | Both [84] | CRC (3), EC (6), stomach (1) | N.d. | Yes/human Polε [45] |
S459F | Somatic | CRC (4) | N.d. | Yes/human Polε [45] |
S297F | Somatic | EC (1), cervical (1) | N.d. | N.d. |
P436R | Somatic | CRC (1) | N.d. | Yes/human Polε [45] |
M444K | Somatic | EC (1) | N.d. | N.d. |
A456P | Somatic | EC (1) | N.d. | N.d. |
APOBEC Family Member | Mutation Motif Preference | Cellular Localization | Expression Correlates with TCW Mutations in Tumors | Evidence for Mutation during Transcription | Evidence for Mutation during Replication | Evidence for Mutation during DSB Repair | References |
---|---|---|---|---|---|---|---|
AID | WRC | Cytoplasmic | N/A | Yes | Yes | Yes | [112,113,114,115,116] |
APOBEC1 | TCW | Pan Cellular | N.d. | N.d. | N.d. | N.d. | ˗ |
APOBEC2 | N.d. | N.d. | N.d. | N.d. | N.d. | N.d. | ˗ |
APOBEC3A | TCW | Pan Cellular | Yes | Limited | Yes | Yes | [116,117,118] |
APOBEC3B | TCW | Nuclear | Yes | Limited | Yes | Yes | [116,117] |
APOBEC3C | TCW | Pan Cellular | No | N.d. | N.d. | N.d. | ˗ |
APOBEC3D/E | TCW | Cytoplasmic | No | N.d. | N.d. | N.d. | ˗ |
APOBEC3F | TCW | Cytoplasmic | No | N.d. | N.d. | N.d. | ˗ |
APOBEC3G | CC | Cytoplasmic | N/A | Limited | Yes | N.d. | [116] |
APOBEC3H | TCW | Cytoplasmic | No | N.d. | N.d. | N.d. | ˗ |
APOBEC4 | N.d. | N.d. | N.d. | N.d. | N.d. | N.d. | ˗ |
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Mertz, T.M.; Harcy, V.; Roberts, S.A. Risks at the DNA Replication Fork: Effects upon Carcinogenesis and Tumor Heterogeneity. Genes 2017, 8, 46. https://doi.org/10.3390/genes8010046
Mertz TM, Harcy V, Roberts SA. Risks at the DNA Replication Fork: Effects upon Carcinogenesis and Tumor Heterogeneity. Genes. 2017; 8(1):46. https://doi.org/10.3390/genes8010046
Chicago/Turabian StyleMertz, Tony M., Victoria Harcy, and Steven A. Roberts. 2017. "Risks at the DNA Replication Fork: Effects upon Carcinogenesis and Tumor Heterogeneity" Genes 8, no. 1: 46. https://doi.org/10.3390/genes8010046
APA StyleMertz, T. M., Harcy, V., & Roberts, S. A. (2017). Risks at the DNA Replication Fork: Effects upon Carcinogenesis and Tumor Heterogeneity. Genes, 8(1), 46. https://doi.org/10.3390/genes8010046