Disparate contributions of the Fanconi anemia pathway and homologous recombination in preventing spontaneous mutagenesis.
Fanconi anemia (FA) is a chromosomal instability disorder in which DNA-damage processing defects are reported for translesion synthesis (TLS), non-homologous end joining (NHEJ) and homologous recombination (HR; both increased and decreased). To reconcile these diverse findings, we compared spontaneous mutagenesis in FA and HR mutants of hamster CHO cells. In the fancg mutant we find a reduced mutation rate accompanied by an increased proportion of deletions within the hprt gene. Moreover, in fancg cells gene amplification at the CAD and dhfr loci is elevated, another manifestation of inappropriate processing of damage during DNA replication. In contrast, the rad51d HR mutant has a greatly elevated rate of hprt mutations, >85% of which are deletions. Our analysis supports the concept that HR faithfully restores broken replication forks, whereas the FA pathway acts more globally to ensure chromosome stability by promoting efficient end joining of replication-derived breaks, as well as TLS and HR.
Hinz
John M
JM
Chemistry, Materials, & Life Sciences Directorate, L441, Lawrence Livermore National Laboratory, P.O. Box 808, Livermore, CA 94551-0808, USA. hinz4@llnl.gov
Nham
Peter B
PB
Urbin
Salustra S
SS
Jones
Irene M
IM
Thompson
Larry H
LH
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D052241:Fanconi Anemia Complementation Group G Protein / Q000235:genetics*; D051856:Fanconi Anemia Complementation Group Proteins / Q000502:physiology; D005784:Gene Amplification; D017353:Gene Deletion; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008957:Models, Genetic; D016296:Mutagenesis; D051135:Rad51 Recombinase / Q000235:genetics*; D011995:Recombination, Genetic; D017384:Sequence Deletion
D052241:Fanconi Anemia Complementation Group G Protein; D051856:Fanconi Anemia Complementation Group Proteins; D007041:Hypoxanthine Phosphoribosyltransferase; D051135:Rad51 Recombinase