POLQ Suppresses Interhomolog Recombination and Loss of Heterozygosity at Targeted DNA Breaks

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2020 Sep 3

PMID 32873648

Citations 15

Authors

Luther Davis

Kevin J Khoo

Yinbo Zhang

Nancy Maizels

Affiliations

Soon will be listed here.

Abstract

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 , which limits breaks available for recombination 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.

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