Nucleic Acids Research Advance Access published online on April 8, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn164
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Nucleic Acid Enzymes |
End-bridging is required for pol µ to efficiently promote repair of noncomplementary ends by nonhomologous end joining
1Department of Biochemistry and Biophysics, 2Lineberger Comprehensive Cancer Center and 3Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, NC 27599, USA
*To whom correspondence should be addressed. Tel: +1 919 966 9809; Fax: +1 919 966 3015; Email: dale_ramsden{at}med.unc.edu
Received December 20, 2007. Revised March 20, 2008. Accepted March 20, 2008.
DNA polymerase µ is a member of the mammalian pol X family and reduces deletion during chromosome break repair by nonhomologous end joining (NHEJ). This biological role is linked to pol µ's ability to promote NHEJ of ends with noncomplementary 3' overhangs, but questions remain regarding how it performs this role. We show here that synthesis by pol µ in this context is often rapid and, despite the absence of primer/template base-pairing, instructed by template. However, pol µ is both much less active and more prone to possible template independence in some contexts, including ends with overhangs longer than two nucleotides. Reduced activity on longer overhangs implies pol µ is less able to synthesize across longer gaps, arguing pol µ must bridge both sides of gaps between noncomplementary ends to be effective in NHEJ. Consistent with this argument, a pol µ mutant defective specifically on gapped substrates is also less active during NHEJ of noncomplementary ends both in vitro and in cells. Taken together, pol µ activity during NHEJ of noncomplementary ends can thus be primarily linked to pol µ's ability to work together with core NHEJ factors to bridge DNA ends and perform a template-dependent gap fill-in reaction.
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