title: Complex Multiple-Nucleotide Substitution Mutations Causing Human Inherited Disease Reveal Novel Insights into the Action of Translesion Synthesis DNA Polymerases.
abstract: Translesion synthesis (TLS) DNA polymerases allow the bypass of unrepaired lesions during DNA replication. Based upon mutational signatures of a subtype of multiple-nucleotide substitution (MNS) mutations causing human inherited disease, we have recently postulated two properties of TLS DNA polymerases in DNA repair, namely, the generation of neo-microhomologies potentiating strand-misalignment, and additional microlesions within the templated inserts when recruited to stalled replication forks. To provide further support for this postulate, we analyzed the mutational signatures of a new and complex subtype of pathogenic MNS mutation. Several mutations containing long templated inserts (8-19 bp) that are highly informative with regard to their underlying mutational mechanisms, harbor imprints of TLS DNA polymerase action. Dissecting the mechanism underlying the generation of the 19-bp insert implicated repeated participation of TLS DNA polymerases in the conversion of a damaged base into a complex MNS lesion through a process of successive template switching and bypass repair.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1078, Brest, France.|Etablissement Français du Sang (EFS) - Bretagne, Brest, France.|Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), Brest, France.
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Chen
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1078, Brest, France.|Etablissement Français du Sang (EFS) - Bretagne, Brest, France.|Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), Brest, France.|Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Centre Hospitalier Universitaire (CHU) Brest, Hôpital Morvan, Brest, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Férec
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
mesh_terms: D004260:DNA Repair; D004261:DNA Replication; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D030342:Genetic Diseases, Inborn / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D054643:INDEL Mutation; D008957:Models, Genetic; D009154:Mutation
chemical_list: D004259:DNA-Directed DNA Polymerase
keywords: MNS; TLS; human inherited disease; multiple-nucleotide substitution mutation; serial replication slippage; template switching; translesion synthesis DNA polymerase