title: Essential Roles for Polymerase θ-Mediated End Joining in the Repair of Chromosome Breaks.
abstract: DNA polymerase theta (Pol θ)-mediated end joining (TMEJ) has been implicated in the repair of chromosome breaks, but its cellular mechanism and role relative to canonical repair pathways are poorly understood. We show that it accounts for most repairs associated with microhomologies and is made efficient by coupling a microhomology search to removal of non-homologous tails and microhomology-primed synthesis across broken ends. In contrast to non-homologous end joining (NHEJ), TMEJ efficiently repairs end structures expected after aborted homology-directed repair (5' to 3' resected ends) or replication fork collapse. It typically does not compete with canonical repair pathways but, in NHEJ-deficient cells, is engaged more frequently and protects against translocation. Cell viability is also severely impaired upon combined deficiency in Pol θ and a factor that antagonizes end resection (Ku or 53BP1). TMEJ thus helps to sustain cell viability and genome stability by rescuing chromosome break repair when resection is misregulated or NHEJ is compromised.
authors.affiliation: Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology, and Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Wyatt
authors.affiliation: Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology, and Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Wanjuan
authors.initials: W
authors.lastname: Feng
authors.affiliation: Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology, and Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Conlin
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78597, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Yousefzadeh
authors.affiliation: School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Roberts
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Mieczkowski
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78597, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Wood
authors.affiliation: Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology, and Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Gaorav P
authors.initials: GP
authors.lastname: Gupta
authors.affiliation: Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology, and Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: dale_ramsden@med.unc.edu.
authors.forename: Dale A
authors.initials: DA
authors.lastname: Ramsden
mesh_terms: D000818:Animals; D064113:CRISPR-Cas Systems; D002461:Cell Line, Transformed; D019457:Chromosome Breakage; D059766:DNA End-Joining Repair; D004259:DNA-Directed DNA Polymerase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D042822:Genomic Instability; D005838:Genotype; D000072200:Ku Autoantigen / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D010641:Phenotype; D013997:Time Factors; D000097462:DNA Polymerase theta
chemical_list: D004259:DNA-Directed DNA Polymerase; D000072200:Ku Autoantigen; D000097462:DNA Polymerase theta; C000606510:Xrcc6 protein, mouse