title: Telomere healing following DNA polymerase arrest-induced breakages is likely the main mechanism generating chromosome 4p terminal deletions.
abstract: Constitutional developmental disorders are frequently caused by terminal chromosomal deletions. The mechanisms and/or architectural features that might underlie those chromosome breakages remain largely unexplored. Because telomeres are the vital DNA protein complexes stabilizing linear chromosomes against chromosome degradation, fusion, and incomplete replication, those terminal-deleted chromosomes acquired new telomeres either by telomere healing or by telomere capture. To unravel the mechanisms leading to chromosomal breakage and healing, we sequenced nine chromosome 4p terminal deletion boundaries. A computational analysis of the breakpoint flanking region, including 12 previously published pure terminal breakage sites, was performed in order to identify architectural features that might be involved in this process. All terminal 4p truncations were likely stabilized by telomerase-mediated telomere healing. In the majority of breakpoints multiple genetic elements have a potential to induce secondary structures and an enrichment in replication stalling site motifs were identified. These findings suggest DNA replication stalling-induced chromosome breakage during early development is the first mechanistic step leading toward terminal deletion syndromes.
authors.affiliation: Centre for Human Genetics, University Hospital, Catholic University of Leuven, Belgium.
authors.forename: Femke
authors.initials: F
authors.lastname: Hannes
authors.forename: Jeroen
authors.initials: J
authors.lastname: Van Houdt
authors.forename: Oliver W
authors.initials: OW
authors.lastname: Quarrell
authors.forename: Martin
authors.initials: M
authors.lastname: Poot
authors.forename: Ron
authors.initials: R
authors.lastname: Hochstenbach
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.forename: Joris R
authors.initials: JR
authors.lastname: Vermeesch
mesh_terms: D001483:Base Sequence; D019457:Chromosome Breakage; D002872:Chromosome Deletion; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D019295:Computational Biology; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D017422:Sequence Analysis, DNA; D016615:Telomere / Q000235:genetics*
chemical_list: D004259:DNA-Directed DNA Polymerase