The fidelity of the ligation step determines how ends are resolved during nonhomologous end joining

Crystal A. Waters, Natasha T. Strande, John M. Pryor, Christina N. Strom, Piotr Mieczkowski, Martin D. Burkhalter, Sehyun Oh, Bahjat F. Qaqish, Dominic T. Moore, Eric A. Hendrickson and Dale A. Ramsden ()
Additional contact information
Crystal A. Waters: Lineberger Comprehensive Cancer Center, University of North Carolina
Natasha T. Strande: Lineberger Comprehensive Cancer Center, University of North Carolina
John M. Pryor: Lineberger Comprehensive Cancer Center, University of North Carolina
Christina N. Strom: Lineberger Comprehensive Cancer Center, University of North Carolina
Piotr Mieczkowski: University of North Carolina
Martin D. Burkhalter: Lineberger Comprehensive Cancer Center, University of North Carolina
Sehyun Oh: Molecular Biology, and Biophysics, University of Minnosota, 6-155 Jackson Hall, 321 Church Street SE
Bahjat F. Qaqish: Biostatistics core, Lineberger Comprehensive Cancer Center, University of North Carolina
Dominic T. Moore: Biostatistics core, Lineberger Comprehensive Cancer Center, University of North Carolina
Eric A. Hendrickson: Molecular Biology, and Biophysics, University of Minnosota, 6-155 Jackson Hall, 321 Church Street SE
Dale A. Ramsden: Lineberger Comprehensive Cancer Center, University of North Carolina

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: Abstract Nonhomologous end joining (NHEJ) can effectively resolve chromosome breaks despite diverse end structures; however, it is unclear how the steps employed for resolution are determined. We sought to address this question by analysing cellular NHEJ of ends with systematically mispaired and damaged termini. We show NHEJ is uniquely proficient at bypassing subtle terminal mispairs and radiomimetic damage by direct ligation. Nevertheless, bypass ability varies widely, with increases in mispair severity gradually reducing bypass products from 85 to 6%. End-processing by nucleases and polymerases is increased to compensate, although paths with the fewest number of steps to generate a substrate suitable for ligation are favoured. Thus, both the frequency and nature of end processing are tailored to meet the needs of the ligation step. We propose a model where the ligase organizes all steps during NHEJ within the stable paired-end complex to limit end processing and associated errors.

Date: 2014
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DOI: 10.1038/ncomms5286

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