Upregulation of error-prone DNA polymerases beta and kappa slows down fork progression without activating the replication checkpoint.
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.
Pillaire
Marie-Jeanne
MJ
Group Instabilité génétique et cancer équipe labellisée par La ligue contre le cancer, Institut de Pharmacologie et de Biologie Structurale, Toulouse Cedex 4, France.
Betous
Rémy
R
Conti
Chiara
C
Czaplicki
Jerzy
J
Pasero
Philippe
P
Bensimon
Aaron
A
Cazaux
Christophe
C
Hoffmann
Jean-Sébastien
JS
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
D019951:DNA Polymerase beta; D004259:DNA-Directed DNA Polymerase; C404302:POLK protein, human; D000099270:Y-Family DNA Polymerases