A Polymerase Theta-dependent repair pathway suppresses extensive genomic instability at endogenous G4 DNA sites.
Genomes contain many sequences that are intrinsically difficult to replicate. Tracts of tandem guanines, for instance, have the potential to adopt stable G-quadruplex structures, which are prone to cause genome alterations. Here we describe G4 DNA-induced mutagenesis in Caenorhabditis elegans and identify a non-canonical DNA break repair mechanism that generates deletions characterized by an extremely narrow size distribution, minimal homology of exactly one nucleotide at the junctions, and by the occasional presence of templated insertions. This typical mutation profile is fully dependent on the A-family polymerase Theta, the absence of which leads to profound loss of sequences surrounding G4 motifs. Theta-mediated end-joining prevails over non-homologous end joining and homologous recombination and prevents genomic havoc at replication fork barriers at the expense of small deletions. G4 DNA-induced deletions also manifest in the genomes of wild isolates of C. elegans, indicating a protective role for this pathway during evolution.
Department of Toxicogenetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
Wouter
W
Koole
Department of Toxicogenetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
Robin
R
van Schendel
Hubrecht Institute-KNAW-Utrecht University Medical Center, Uppsalalaan 8, 3584 CT, The Netherlands.
Andrea E
AE
Karambelas
Department of Toxicogenetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
Jane T
JT
van Heteren
Hubrecht Institute-KNAW-Utrecht University Medical Center, Uppsalalaan 8, 3584 CT, The Netherlands.
Kristy L
KL
Okihara
Department of Toxicogenetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
Marcel
M
Tijsterman
D000818:Animals; D001483:Base Sequence; D017173:Caenorhabditis elegans; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D019143:Evolution, Molecular; D054856:G-Quadruplexes; D008969:Molecular Sequence Data; D000097462:DNA Polymerase theta
D004259:DNA-Directed DNA Polymerase; D000097462:DNA Polymerase theta