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Mateos-Gomez PA, Kent T, Deng SK, McDevitt S, Kashkina E, Hoang TM, Pomerantz RT, Sfeir A
The helicase domain of Poltheta counteracts RPA to promote alt-NHEJ
Nat Struct Mol Biol (2017) 24:1116-1123.
Mammalian polymerase theta (Poltheta) is a multifunctional enzyme that promotes error-prone DNA repair by alternative nonhomologous end joining (alt-NHEJ). Here we present structure-function analyses that reveal that, in addition to the polymerase domain, Poltheta-helicase activity plays a central role during double-strand break (DSB) repair. Our results show that the helicase domain promotes chromosomal translocations by alt-NHEJ in mouse embryonic stem cells and also suppresses CRISPR-Cas9- mediated gene targeting by homologous recombination (HR). In vitro assays demonstrate that Poltheta-helicase activity facilitates the removal of RPA from resected DSBs to allow their annealing and subsequent joining by alt-NHEJ. Consistent with an antagonistic role for RPA during alt-NHEJ, inhibition of RPA1 enhances end joining and suppresses recombination. Taken together, our results reveal that the balance between HR and alt-NHEJ is controlled by opposing activities of Poltheta and RPA, providing further insight into the regulation of repair-pathway choice in mammalian cells.
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Publication Date: 2017-12-01.
Last updated on Tuesday, August 11, 2020