title: Polymerase theta-mediated end joining of replication-associated DNA breaks in C. elegans.
abstract: DNA lesions that block replication fork progression are drivers of cancer-associated genome alterations, but the error-prone DNA repair mechanisms acting on collapsed replication are incompletely understood, and their contribution to genome evolution largely unexplored. Here, through whole-genome sequencing of animal populations that were clonally propagated for more than 50 generations, we identify a distinct class of deletions that spontaneously accumulate in C. elegans strains lacking translesion synthesis (TLS) polymerases. Emerging DNA double-strand breaks are repaired via an error-prone mechanism in which the outermost nucleotide of one end serves to prime DNA synthesis on the other end. This pathway critically depends on the A-family polymerase theta, which protects the genome against gross chromosomal rearrangements. By comparing the genomes of isolates of C. elegans from different geographical regions, we found that in fact most spontaneously evolving structural variations match the signature of polymerase theta-mediated end joining (TMEJ), illustrating that this pathway is an important source of genetic diversification.
authors.affiliation: Department of Toxicogenetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Sophie F
authors.initials: SF
authors.lastname: Roerink
authors.affiliation: Department of Toxicogenetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Robin
authors.initials: R
authors.lastname: van Schendel
authors.affiliation: Department of Toxicogenetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: Tijsterman
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D004261:DNA Replication; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism*; D049751:Genome, Helminth; D056914:Genomic Structural Variation; D000097462:DNA Polymerase theta
chemical_list: D029742:Caenorhabditis elegans Proteins; D004259:DNA-Directed DNA Polymerase; D000097462:DNA Polymerase theta