title: Upregulation of error-prone DNA polymerases beta and kappa slows down fork progression without activating the replication checkpoint.
abstract: There is rising evidence that cancer development is associated from its earliest stages with DNA replication stress, a major source of spontaneous genomic instability. However, the origin of these replication defects has remained unclear. We have investigated the consequences of upregulating error-prone DNA polymerases (pol) beta and kappa on chromosomal DNA replication. These enzymes are misregulated in different types of cancers and induce major chromosomal instabilities when overexpressed at low levels. Here, we have used DNA combing to show that a moderate overexpression of pol beta or pol kappa is sufficient to impede replication fork progression and to promote the activation of additional replication origins. Interestingly, alterations of the normal replication program induced by excess error-prone polymerases were not detected by the replication checkpoint. We therefore propose that upregulation of error-prone DNA polymerases induces a checkpoint-blind replication stress that contributes to genomic instability and to cancer development.
authors.affiliation: Group Instabilité génétique et cancer équipe labellisée par La ligue contre le cancer, Institut de Pharmacologie et de Biologie Structurale, Toulouse Cedex 4, France.
authors.forename: Marie-Jeanne
authors.initials: MJ
authors.lastname: Pillaire
authors.forename: Rémy
authors.initials: R
authors.lastname: Betous
authors.forename: Chiara
authors.initials: C
authors.lastname: Conti
authors.forename: Jerzy
authors.initials: J
authors.lastname: Czaplicki
authors.forename: Philippe
authors.initials: P
authors.lastname: Pasero
authors.forename: Aaron
authors.initials: A
authors.lastname: Bensimon
authors.forename: Christophe
authors.initials: C
authors.lastname: Cazaux
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Hoffmann
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D019951:DNA Polymerase beta / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication / Q000235:genetics / Q000502:physiology*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism*; D042822:Genomic Instability; D006801:Humans; D008957:Models, Genetic; D016196:S Phase / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation; D000099270:Y-Family DNA Polymerases
chemical_list: D019951:DNA Polymerase beta; D004259:DNA-Directed DNA Polymerase; C404302:POLK protein, human; D000099270:Y-Family DNA Polymerases