title: A concomitant loss of dormant origins and FANCC exacerbates genome instability by impairing DNA replication fork progression.
abstract: Accumulating evidence suggests that dormant DNA replication origins play an important role in the recovery of stalled forks. However, their functional interactions with other fork recovery mechanisms have not been tested. We previously reported intrinsic activation of the Fanconi anemia (FA) pathway in a tumor-prone mouse model (Mcm4chaos3) with a 60% loss of dormant origins. To understand this further, we introduced a null allele of Fancc (Fancc-), encoding a member of the FA core complex, into the Mcm4chaos3 background. Primary embryonic fibroblasts double homozygous for Mcm4chaos3 and Fancc- (Mcm4chaos3/chaos3;Fancc-/-) showed significantly increased levels of markers of stalled/collapsed forks compared to either single homozygote. Interestingly, a loss of dormant origins also increased the number of sites in which replication was delayed until prophase, regardless of FA pathway activation. These replication defects coincided with substantially elevated levels of genome instability in Mcm4chaos3/chaos3;Fancc-/- cells, resulting in a high rate of perinatal lethality of Mcm4chaos3/chaos3;Fancc-/- mice and the accelerated tumorigenesis of surviving mice. Together, these findings uncover a specialized role of dormant origins in replication completion while also identifying important functional overlaps between dormant origins and the FA pathway in maintaining fork progression, genome stability, normal development and tumor suppression.
authors.affiliation: Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA Molecular, Cellular, Developmental Biology and Genetics Program, University of Minnesota, Minneapolis, MN 55455, USA shima023@umn.edu.
authors.forename: Spencer W
authors.initials: SW
authors.lastname: Luebben
authors.affiliation: Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA shima023@umn.edu.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kawabata
authors.affiliation: Masonic Cancer Center, Minneapolis, MN 55455, USA College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Johnson
authors.affiliation: Masonic Cancer Center, Minneapolis, MN 55455, USA College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA.
authors.forename: M Gerard
authors.initials: MG
authors.lastname: O'Sullivan
authors.affiliation: Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA Masonic Cancer Center, Minneapolis, MN 55455, USA shima023@umn.edu.
authors.forename: Naoko
authors.initials: N
authors.lastname: Shima
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000235:genetics; D002478:Cells, Cultured; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism; D005199:Fanconi Anemia / Q000235:genetics; D052218:Fanconi Anemia Complementation Group C Protein / Q000172:deficiency / Q000235:genetics*; D042822:Genomic Instability; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015162:Micronucleus Tests; D064148:Minichromosome Maintenance Complex Component 4 / Q000235:genetics / Q000378:metabolism; D059807:S Phase Cell Cycle Checkpoints; D015398:Signal Transduction; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C497652:Fancc protein, mouse; D052218:Fanconi Anemia Complementation Group C Protein; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1; C516793:Mcm4 protein, mouse; D064148:Minichromosome Maintenance Complex Component 4