The faithful propagation of species requires a complex balance of DNA-repair pathways to maintain genome integrity. New work sheds light on one such poorly understood pathway and its role in certain cancers. See Letters p.254 & p.258
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Cho, N., Greenberg, R. Familiar ends with alternative endings. Nature 518, 174–175 (2015). https://doi.org/10.1038/nature14200
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DOI: https://doi.org/10.1038/nature14200
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DNA replication machinery prevents Rad52-dependent single-strand annealing that leads to gross chromosomal rearrangements at centromeres
Communications Biology (2020)
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Dual loss of human POLQ and LIG4 abolishes random integration
Nature Communications (2017)
Aidan Doherty
Two papers in this issue of Nature (Mateos-Gomez et al. an Ceccaldi et al.) and another in Nature Structural and Molecular Biology (Kent et al.) report a role for PolQ in promoting DNA double-strand break (DSB) repair in eukaryotic cells by the so-called microhomology-mediated end-joining (MMEJ) pathway. However, it is important to appreciate that this form of end-joining also exists in the other domains of life and the molecular details of a prokaryotic MMEJ repair process have been described (Brissett et al, 2007; 2011; 2013).
NHEJ is not a eukaryotic-specific repair pathway but, as identified over a decade ago, this break repair process first originated in prokaryotes and archaea (Weller et al., 2002; Della et al., 2004; Bartlett, et al., 2013). This DSB repair pathway subsequently became more complex by the acquisition of additional factors during its evolution in eukaryotes. Despite these differences, the basic mechanisms of DSB repair are likely to be similar and this is particularly true for MMEJ. The mycobacterial NHEJ repair apparatus has provided unexpected molecular insights into how break repair polymerases (PolDom/ LigD Pol) bind to the termini of DSBs, promote break synapsis via MMEJ and extend in trans from annealed 3 prime overhangs (Brissett et al, 2007, 2011, 2013). It appears that MMEJ first arose in prokaryotes, becoming the predominant break repair mechanism in stationary phase (Pitcher et al., 2007), with the polymerase playing a central role in promoting this process. Given that these enzymes (PolDom and PolQ) share a variety of atypical extension and end-synapsis activities (Hogg et al., 2012; Kent et al., 2015), the mechanistic studies on prokaryotic end-joining are likely to be also informative about PolQ's role in MMEJ.