The DOI matches its Crossref record; 67 of the 67 references it cites were found in a registry or an index.
Mechanism of Suppression of Chromosomal Instability by DNA Polymerase POLQ
Open accessAbstract
Although a defect in the DNA polymerase POLQ leads to ionizing radiation sensitivity in mammalian cells, the relevant enzymatic pathway has not been identified. Here we define the specific mechanism by which POLQ restricts harmful DNA instability. Our experiments show that Polq-null murine cells are selectively hypersensitive to DNA strand breaking agents, and that damage resistance requires the DNA polymerase activity of POLQ. Using a DNA break end joining assay in cells, we monitored repair of DNA ends with long 3' single-stranded overhangs. End joining events retaining much of the overhang were dependent on POLQ, and independent of Ku70. To analyze the repair function in more detail, we examined immunoglobulin class switch joining between DNA segments in antibody genes. POLQ participates in end joining of a DNA break during immunoglobulin class-switching, producing insertions of base pairs at the joins with homology to IgH switch-region sequences. Biochemical experiments with purified human POLQ protein revealed the mechanism generating the insertions during DNA end joining, relying on the unique ability of POLQ to extend DNA from minimally paired primers. DNA breaks at the IgH locus can sometimes join with breaks in Myc, creating a chromosome translocation. We found a marked increase in Myc/IgH translocations in Polq-defective mice, showing that POLQ suppresses genomic instability and genome rearrangements originating at DNA double-strand breaks. This work clearly defines a role and mechanism for mammalian POLQ in an alternative end joining pathway that suppresses the formation of chromosomal translocations. Our findings depart from the prevailing view that alternative end joining processes are generically translocation-prone.
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Cites
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Self-citationFanconi anaemia and the repair of Watson and Crick DNA crosslinks
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AID Is Required for the Chromosomal Breaks in c-myc that Lead to c-myc/IgH Translocations
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Non-homologous DNA end joining and alternative pathways to double-strand break repair
Chang, H. H. Y., Pannunzio, N. R., Adachi, N., & Lieber, M. R. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.48 · Cited by 1,757
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Scully, R., Panday, A., Elango, R., & Willis, N. A. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0152-0 · Cited by 1,457
Targeting DNA damage response pathways in cancer
Groelly, F. J., Fawkes, M., Dagg, R. A., Blackford, A. N., & Tarsounas, M. (2023) · Nature Reviews Cancer · doi:10.1038/s41568-022-00535-5 · Cited by 836
Mechanisms underlying structural variant formation in genomic disorders
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Microhomology-Mediated End Joining: A Back-up Survival Mechanism or Dedicated Pathway?
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Metadata
- Authors
- Yousefzadeh, M. J., Wyatt, D. W., Takata, K.-I., Mu, Y., Hensley, S. C., Tomida, J., Bylund, G. O., Doublié, S., Johansson, E., Ramsden, D. A., McBride, K. M., & Wood, R. D.
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-10-02
- Volume
- 10
- Issue
- 10
- Pages
- e1004654
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- OpenAlex
- W1976924852
- Cited by
- 277
- References
- 67
- FWCI
- 8.64
- Type
- journal article
- Language
- en
- Open access
- gold
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- Yousefzadeh, M. J., Wyatt, D. W., Takata, K.-I., Mu, Y., Hensley, S. C., Tomida, J., Bylund, G. O., Doublié, S., Johansson, E., Ramsden, D. A., McBride, K. M., & Wood, R. D. (2014). Mechanism of Suppression of Chromosomal Instability by DNA Polymerase POLQ. PLoS Genetics. https://doi.org/10.1371/journal.pgen.1004654
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