Mutagenic Natural Genetic Engineering Activities

Mutation Type

Biochemical Activity

References

Single nucleotide substitutions

Y-family mutagenic trans-lesion DNA polymerase

(Napolitano, Janel-Bintz et al. 2000; Goodman 2002; Guo, Kosarek-Stancel et al. 2009; Andersson, Koskiniemi et al. 2010)

Frameshifts

Y-family mutagenic trans-lesion DNA polymerase

(Napolitano, Janel-Bintz et al. 2000; Goodman 2002; Guo, Kosarek-Stancel et al. 2009; Andersson, Koskiniemi et al. 2010)

Deletions (bacteria)

Y-family mutagenic trans-lesion DNA polymerase

(Koskiniemi and Andersson 2009)

Deletions and translocations (often involving sequence microhomologies)

Mre11, CltP exonucleases; canonical or alternative non-homologous end-joining (NHEJ) complexes

(Ikeda, Shiraishi et al. 2004; Shrivastav, De Haro et al. 2008; Takahashi, Jin et al. 2009; Vissers, Bhatt et al. 2009; Zhuang, Jiang et al. 2009; Glover, Jun et al. 2011; Simsek, Brunet et al. 2011; Zhang and Jasin 2011; Villarreal, Lee et al. 2012; Bindra, Goglia et al. 2013; Verdin, D'Haene et al. 2013; Ghezraoui, Piganeau et al. 2014)

Deletions and translocations

Non-allelic homologous recombination (NAHR) between mobile DNA repeats

(Sen, Han et al. 2006; Hoang, Tan et al. 2010; McVean 2010; Robberecht, Voet et al. 2013)

Deletion

Elevated transcription, Topoisomerase I

(Takahashi, Burguiere-Slezak et al. 2011)

Deletion

LINE 1-mediated

(Gilbert, Lutz-Prigge et al. 2002; Han, Sen et al. 2005; Han, Lee et al. 2008)

Deletion

Alu-Alu NAHR

(Callinan, Wang et al. 2005; Sen, Han et al. 2006; de Smith, Walters et al. 2008; Franke, Bausch et al. 2009; Morales, White et al. 2015)

Deletion

SVA-mediated NAHR

(Lee, Ha et al. 2012; Vogt, Bengesser et al. 2014)

Deletion

sRNA-targeted deletion

(Swart and Nowacki 2015)

Translocations

Nonhomologous end joining or microhomology-mediated break-induced replication

(Weckselblatt, Hermetz et al. 2015)

Somatic hypermutation and kataegis:  multiple clustered nucleotide substitutions

AID or APOBEC cytosine deaminase

(Peled, Kuang et al. 2008; Lada, Dhar et al. 2012; Jaszczur, Bertram et al. 2013; Taylor, Nik-Zainal et al. 2013; Sakofsky, Roberts et al. 2014; Maciejowski, Li et al. 2015; Goodman 2016)

Chromothripsis and complex chromosome segment insertions

Loss of p53-dependent checkpoints; replication-based mechanisms with iterative template switches; Rad51 homologous recombination; NHEJ; telomere ligation and breakage-fusion-bridge (BFB) cycle of dicentric product; premature chromosome condensation; segregation of chromosome breakage and repair in micronucleus. (Not all these processes are involved in each chromothripsis event.)

(Haaf, Raderschall et al. 1999; Chiang, Jacobsen et al. 2012; Crasta, Ganem et al. 2012; Kloosterman, Tavakoli-Yaraki et al. 2012; Pellestor, Gatinois et al. 2014; Pellestor, Gatinois et al. 2014; Leibowitz, Zhang et al. 2015; Maciejowski, Li et al. 2015; Terzoudi, Karakosta et al. 2015; Zhang, Spektor et al. 2015; Poot 2016; Storchova and Kloosterman 2016; Poot 2017) (Iliakis, Wang et al. 2004; Gu, Szafranski et al. 2016; Masset, Hestand et al. 2016)

Chromothripsis (chromosome shattering)

L1-Mediated Retrotransposition and Alu/Alu Homologous Recombination

(Nazaryan-Petersen, Bertelsen et al. 2016)

 

 

REFERENCES

 

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Bindra, R. S., A. G. Goglia, et al. (2013). "Development of an assay to measure mutagenic non-homologous end-joining repair activity in mammalian cells." Nucleic Acids Res 41(11): e115. http://www.ncbi.nlm.nih.gov/pubmed/23585275.

Callinan, P. A., J. Wang, et al. (2005). "Alu retrotransposition-mediated deletion." J Mol Biol 348(4): 791-800. http://www.ncbi.nlm.nih.gov/pubmed/15843013.

Chiang, C., J. C. Jacobsen, et al. (2012). "Complex reorganization and predominant non-homologous repair following chromosomal breakage in karyotypically balanced germline rearrangements and transgenic integration." Nat Genet 44(4): 390-397, S391. http://www.ncbi.nlm.nih.gov/pubmed/22388000.

Crasta, K., N. J. Ganem, et al. (2012). "DNA breaks and chromosome pulverization from errors in mitosis." Nature 482(7383): 53-58. http://www.ncbi.nlm.nih.gov/pubmed/22258507.

de Smith, A. J., R. G. Walters, et al. (2008). "Small deletion variants have stable breakpoints commonly associated with alu elements." PLoS One 3(8): e3104. http://www.ncbi.nlm.nih.gov/pubmed/18769679.

Franke, G., B. Bausch, et al. (2009). "Alu-Alu recombination underlies the vast majority of large VHL germline deletions: Molecular characterization and genotype-phenotype correlations in VHL patients." Hum Mutat 30(5): 776-786. http://www.ncbi.nlm.nih.gov/pubmed/19280651.

Ghezraoui, H., M. Piganeau, et al. (2014). "Chromosomal translocations in human cells are generated by canonical nonhomologous end-joining." Mol Cell 55(6): 829-842. http://www.ncbi.nlm.nih.gov/pubmed/25201414.

Gilbert, N., S. Lutz-Prigge, et al. (2002). "Genomic deletions created upon LINE-1 retrotransposition." Cell 110(3): 315-325. http://www.ncbi.nlm.nih.gov/pubmed/12176319.

Glover, L., J. Jun, et al. (2011). "Microhomology-mediated deletion and gene conversion in African trypanosomes." Nucleic Acids Res 39(4): 1372-1380. http://www.ncbi.nlm.nih.gov/pubmed/20965968.

Goodman, M. F. (2002). "Error-prone repair DNA polymerases in prokaryotes and eukaryotes." Annu Rev Biochem 71: 17-50. http://www.ncbi.nlm.nih.gov/pubmed/12045089.

Goodman, M. F. (2016). "Better living with hyper-mutation." Environ Mol Mutagen 57(6): 421-434. http://www.ncbi.nlm.nih.gov/pubmed/27273795.

Gu, S., P. Szafranski, et al. (2016). "Mechanisms for Complex Chromosomal Insertions." PLoS Genet 12(11): e1006446. http://www.ncbi.nlm.nih.gov/pubmed/27880765.

Guo, C., J. N. Kosarek-Stancel, et al. (2009). "Y-family DNA polymerases in mammalian cells." Cell Mol Life Sci\ 66(14): 2363-2381. http://www.ncbi.nlm.nih.gov/pubmed/19367366.

Haaf, T., E. Raderschall, et al. (1999). "Sequestration of mammalian Rad51-recombination protein into micronuclei." J Cell Biol 144(1): 11-20. http://www.ncbi.nlm.nih.gov/pubmed/9885240.

Han, K., J. Lee, et al. (2008). "L1 recombination-associated deletions generate human genomic variation." Proc Natl Acad Sci U S A 105(49): 19366-19371. http://www.ncbi.nlm.nih.gov/pubmed/19036926.

Han, K., S. K. Sen, et al. (2005). "Genomic rearrangements by LINE-1 insertion-mediated deletion in the human and chimpanzee lineages." Nucleic Acids Res 33(13): 4040-4052. http://www.ncbi.nlm.nih.gov/pubmed/16034026.

Hoang, M. L., F. J. Tan, et al. (2010). "Competitive repair by naturally dispersed repetitive DNA during non-allelic homologous recombination." PLoS Genet 6(12): e1001228. http://www.ncbi.nlm.nih.gov/pubmed/21151956.

Ikeda, H., K. Shiraishi, et al. (2004). "Illegitimate recombination mediated by double-strand break and end-joining in Escherichia coli." Adv Biophys 38: 3-20. http://www.ncbi.nlm.nih.gov/pubmed/15493325.

Iliakis, G., H. Wang, et al. (2004). "Mechanisms of DNA double strand break repair and chromosome aberration formation." Cytogenet Genome Res 104(1-4): 14-20. http://www.ncbi.nlm.nih.gov/pubmed/15162010.

Jaszczur, M., J. G. Bertram, et al. (2013). "AID and Apobec3G haphazard deamination and mutational diversity." Cell Mol Life Sci 70(17): 3089-3108. http://www.ncbi.nlm.nih.gov/pubmed/23178850.

Kloosterman, W. P., M. Tavakoli-Yaraki, et al. (2012). "Constitutional chromothripsis rearrangements involve clustered double-stranded DNA breaks and nonhomologous repair mechanisms." Cell Rep 1(6): 648-655. http://www.ncbi.nlm.nih.gov/pubmed/22813740.

Koskiniemi, S. and D. I. Andersson (2009). "Translesion DNA polymerases are required for spontaneous deletion formation in Salmonella typhimurium." Proc Natl Acad Sci U S A 106(25): 10248-10253. http://www.ncbi.nlm.nih.gov/pubmed/19525399.

Lada, A. G., A. Dhar, et al. (2012). "AID/APOBEC cytosine deaminase induces genome-wide kataegis." Biol Direct 7: 47; discussion 47. http://www.ncbi.nlm.nih.gov/pubmed/23249472.

Lee, J., J. Ha, et al. (2012). "Human Genomic Deletions Generated by SVA-Associated Events." Comp Funct Genomics 2012: 807270. http://www.ncbi.nlm.nih.gov/pubmed/22666087.

Leibowitz, M. L., C. Z. Zhang, et al. (2015). "Chromothripsis: A New Mechanism for Rapid Karyotype Evolution." Annu Rev Genet 49: 183-211. http://www.ncbi.nlm.nih.gov/pubmed/26442848.

Maciejowski, J., Y. Li, et al. (2015). "Chromothripsis and Kataegis Induced by Telomere Crisis." Cell 163(7): 1641-1654. http://www.ncbi.nlm.nih.gov/pubmed/26687355.

Masset, H., M. S. Hestand, et al. (2016). "A Distinct Class of Chromoanagenesis Events Characterized by Focal Copy Number Gains." Hum Mutat 37(7): 661-668. http://www.ncbi.nlm.nih.gov/pubmed/26936114.

McVean, G. (2010). "What drives recombination hotspots to repeat DNA in humans?" Philos Trans R Soc Lond B Biol Sci 365(1544): 1213-1218. http://www.ncbi.nlm.nih.gov/pubmed/20308096.

Morales, M. E., T. B. White, et al. (2015). "The contribution of alu elements to mutagenic DNA double-strand break repair." PLoS Genet 11(3): e1005016. http://www.ncbi.nlm.nih.gov/pubmed/25761216.

Napolitano, R., R. Janel-Bintz, et al. (2000). "All three SOS-inducible DNA polymerases (Pol II, Pol IV and Pol V) are involved in induced mutagenesis." Embo J 19(22): 6259-6265. http://www.ncbi.nlm.nih.gov/pubmed/11080171.

Nazaryan-Petersen, L., B. Bertelsen, et al. (2016). "Germline Chromothripsis Driven by L1-Mediated Retrotransposition and Alu/Alu Homologous Recombination." Hum Mutat 37(4): 385-395. http://www.ncbi.nlm.nih.gov/pubmed/26929209.

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Pellestor, F., V. Gatinois, et al. (2014). "[Chromothripsis, an unexpected novel form of complexity for chromosomal rearrangements]." Med Sci (Paris) 30(3): 266-273. http://www.ncbi.nlm.nih.gov/pubmed/24685217.

Pellestor, F., V. Gatinois, et al. (2014). "Chromothripsis: potential origin in gametogenesis and preimplantation cell divisions. A review." Fertil Steril 102(6): 1785-1796. http://www.ncbi.nlm.nih.gov/pubmed/25439810.

Poot, M. (2016). "Chromothripsis after Stumbling through DNA Replication." Mol Syndromol 6(5): 207-209. http://www.ncbi.nlm.nih.gov/pubmed/26997940.

Poot, M. (2017). "Of Simple and Complex Genome Rearrangements, Chromothripsis, Chromoanasynthesis, and Chromosome Chaos." Mol Syndromol 8(3): 115-117. http://www.ncbi.nlm.nih.gov/pubmed/28588432.

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Sakofsky, C. J., S. A. Roberts, et al. (2014). "Break-induced replication is a source of mutation clusters underlying kataegis." Cell Rep 7(5): 1640-1648. http://www.ncbi.nlm.nih.gov/pubmed/24882007.

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Simsek, D., E. Brunet, et al. (2011). "DNA Ligase III Promotes Alternative Nonhomologous End-Joining during Chromosomal Translocation Formation." PLoS Genet 7(6): e1002080. http://www.ncbi.nlm.nih.gov/pubmed/21655080.

Storchova, Z. and W. P. Kloosterman (2016). "The genomic characteristics and cellular origin of chromothripsis." Curr Opin Cell Biol 40: 106-113. http://www.ncbi.nlm.nih.gov/pubmed/27023493.

Swart, E. C. and M. Nowacki (2015). "The eukaryotic way to defend and edit genomes by sRNA-targeted DNA deletion." Ann N Y Acad Sci. http://www.ncbi.nlm.nih.gov/pubmed/25581723.

Takahashi, T., G. Burguiere-Slezak, et al. (2011). "Topoisomerase 1 provokes the formation of short deletions in repeated sequences upon high transcription in Saccharomyces cerevisiae." Proceedings of the National Academy of Sciences 108(2): 692-697. .

Takahashi, T., F. J. Jin, et al. (2009). "Nonhomologous end-joining deficiency allows large chromosomal deletions to be produced by replacement-type recombination in Aspergillus oryzae." Fungal Genet Biol 46(11): 815-824. http://www.ncbi.nlm.nih.gov/pubmed/19654050.

Taylor, B. J., S. Nik-Zainal, et al. (2013). "DNA deaminases induce break-associated mutation showers with implication of APOBEC3B and 3A in breast cancer kataegis." Elife 2: e00534. http://www.ncbi.nlm.nih.gov/pubmed/23599896.

Terzoudi, G. I., M. Karakosta, et al. (2015). "Stress induced by premature chromatin condensation triggers chromosome shattering and chromothripsis at DNA sites still replicating in micronuclei or multinucleate cells when primary nuclei enter mitosis." Mutat Res Genet Toxicol Environ Mutagen 793: 185-198. http://www.ncbi.nlm.nih.gov/pubmed/26520389.

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Zhang, Y. and M. Jasin (2011). "An essential role for CtIP in chromosomal translocation formation through an alternative end-joining pathway." Nat Struct Mol Biol 18(1): 80-84. http://www.ncbi.nlm.nih.gov/pubmed/21131978.

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