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POLQ suppresses interhomolog recombination and loss of heterozygosity at targeted DNA breaks

Significance This manuscript identifies a pathway of recombination which joins DNA ends on two homologous chromosomes in human cells. This pathway supports efficient recombination at targeted DSBs and nicks, at frequencies exceeding those of the spontaneous recombination events that ameliorate genetic diseases in human blood and skin cells. Recombination is further stimulated by depletion of POLQ, a factor with both DNA polymerase and helicase activities. POLQ depletion causes an especially dramatic increase in the frequency of copy-neutral loss of heterozygosity (cnLOH) events. These results have immediate practical implications for therapeutic correction of both compound heterozygous and autosomal dominant mutations, and they identify a mechanistic origin for prominent but poorly understood mutagenic signatures in cancer. Interhomolog recombination (IHR) occurs spontaneously in somatic human cells at frequencies that are low but sufficient to ameliorate some genetic diseases caused by heterozygous mutations or autosomal dominant mutations. Here we demonstrate that DNA nicks or double-strand breaks (DSBs) targeted by CRISPR-Cas9 to both homologs can stimulate IHR and associated copy-neutral loss of heterozygosity (cnLOH) in human cells. The frequency of IHR is 10-fold lower at nicks than at DSBs, but cnLOH is evident in a greater fraction of recombinants. IHR at DSBs occurs predominantly via reciprocal end joining. At DSBs, depletion of POLQ caused a dramatic increase in IHR and in the fraction of recombinants exhibiting cnLOH, suggesting that POLQ promotes end joining in cis, which limits breaks available for recombination in trans. These results define conditions that may produce cnLOH as a mutagenic signature in cancer and may, conversely, promote therapeutic correction of both compound heterozygous and dominant negative mutations associated with genetic disease.