title: A Signature of Genomic Instability Resulting from Deficient Replication Licensing.
abstract: Insufficient licensing of DNA replication origins has been shown to result in genome instability, stem cell deficiency, and cancers. However, it is unclear whether the DNA damage resulting from deficient replication licensing occurs generally or if specific sites are preferentially affected. To map locations of ongoing DNA damage in vivo, the DNAs present in red blood cell micronuclei were sequenced. Many micronuclei are the product of DNA breaks that leave acentromeric remnants that failed to segregate during mitosis and should reflect the locations of breaks. To validate the approach we show that micronuclear sequences identify known common fragile sites under conditions that induce breaks at these locations (hydroxyurea). In MCM2 deficient mice a different set of preferred breakage sites is identified that includes the tumor suppressor gene Tcf3, which is known to contribute to T-lymphocytic leukemias that arise in these mice, and the 45S rRNA gene repeats.
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors.forename: Steven C
authors.identifier: http://orcid.org/0000-0002-3966-8214
authors.initials: SC
authors.lastname: Pruitt
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors.forename: Maochun
authors.initials: M
authors.lastname: Qin
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors.forename: Dimiter
authors.initials: D
authors.lastname: Kunnev
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors.forename: Amy
authors.initials: A
authors.lastname: Freeland
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D004249:DNA Damage; D004261:DNA Replication; D004912:Erythrocytes / Q000473:pathology; D042822:Genomic Instability; D051379:Mice; D048629:Micronuclei, Chromosome-Defective; D015162:Micronucleus Tests / Q000379:methods*; D064111:Minichromosome Maintenance Complex Component 2 / Q000172:deficiency / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D064111:Minichromosome Maintenance Complex Component 2; C576318:Mcm2 protein, mouse; C075668:Tcf3 protein, mouse