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Kent T, Chandramouly G, McDevitt SM, Ozdemir AY, Pomerantz RT
Mechanism of microhomology-mediated end-joining promoted by human DNA polymerase theta
Nat Struct Mol Biol (2015) 22:230-7.
Abstract
Microhomology-mediated end-joining (MMEJ) is an error-prone alternative double-strand break-repair pathway that uses sequence microhomology to recombine broken DNA. Although MMEJ has been implicated in cancer development, the mechanism of this pathway is unknown. We demonstrate that purified human DNA polymerase theta (Poltheta) performs MMEJ of DNA containing 3' single-strand DNA overhangs with >/=2 bp of homology, including DNA modeled after telomeres, and show that MMEJ is dependent on Poltheta in human cells. Our data support a mechanism whereby Poltheta facilitates end-joining and microhomology annealing, then uses the opposing overhang as a template in trans to stabilize the DNA synapse. Poltheta exhibits a preference for DNA containing a 5'-terminal phosphate, similarly to polymerases involved in nonhomologous end-joining. Finally, we identify a conserved loop domain that is essential for MMEJ and higher-order structures of Poltheta that probably promote DNA synapse formation.
Note
Publication Date: 2015-03-01.
PMCID: PMC4351179
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Last updated on Monday, November 04, 2019