title: Bloom syndrome radials are predominantly non-homologous and are suppressed by phosphorylated BLM.
abstract: Biallelic mutations in BLM cause Bloom syndrome (BS), a genome instability disorder characterized by growth retardation, sun sensitivity and a predisposition to cancer. As evidence of decreased genome stability, BS cells demonstrate not only elevated levels of spontaneous sister chromatid exchanges (SCEs), but also exhibit chromosomal radial formation. The molecular nature and mechanism of radial formation is not known, but radials have been thought to be DNA recombination intermediates between homologs that failed to resolve. However, we find that radials in BS cells occur over 95% between non-homologous chromosomes, and occur non-randomly throughout the genome. BLM must be phosphorylated at T99 and T122 for certain cell cycle checkpoints, but it is not known whether these modifications are necessary to suppress radial formation. We find that exogenous BLM constructs preventing phosphorylation at T99 and T122 are not able to suppress radial formation in BS cells, but are able to inhibit SCE formation. These findings indicate that BLM functions in 2 distinct pathways requiring different modifications. In one pathway, for which the phosphorylation marks appear dispensable, BLM functions to suppress SCE formation. In a second pathway, T99 and T122 phosphorylations are essential for suppression of chromosomal radial formation, both those formed spontaneously and those formed following interstrand crosslink damage.
authors.affiliation: Department of Molecular and Medical Genetics Oregon Health & Science University, 3181 SW Sam Jackson Park, Portland, OR 97239.
authors.forename: Nichole
authors.initials: N
authors.lastname: Owen
authors.affiliation: Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501 Japan.
authors.forename: James
authors.initials: J
authors.lastname: Hejna
authors.affiliation: Department of Molecular and Medical Genetics Oregon Health & Science University, 3181 SW Sam Jackson Park, Portland, OR 97239.
authors.forename: Scott
authors.initials: S
authors.lastname: Rennie
authors.affiliation: Department of Molecular and Medical Genetics Oregon Health & Science University, 3181 SW Sam Jackson Park, Portland, OR 97239.
authors.forename: Asia
authors.initials: A
authors.lastname: Mitchell
authors.affiliation: Department of Molecular and Medical Genetics Oregon Health & Science University, 3181 SW Sam Jackson Park, Portland, OR 97239.
authors.forename: Amy Hanlon
authors.initials: AH
authors.lastname: Newell
authors.affiliation: Department of Molecular and Medical Genetics Oregon Health & Science University, 3181 SW Sam Jackson Park, Portland, OR 97239.
authors.forename: Navid
authors.initials: N
authors.lastname: Ziaie
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine Houston, TX 77030.
authors.forename: Robb E
authors.initials: RE
authors.lastname: Moses
authors.affiliation: Department of Molecular and Medical Genetics Oregon Health & Science University, 3181 SW Sam Jackson Park, Portland, OR 97239.
authors.forename: Susan B
authors.initials: SB
authors.lastname: Olson
mesh_terms: D001816:Bloom Syndrome / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D043171:Chromosomal Instability; D002877:Chromosomes, Human / Q000235:genetics; D006801:Humans; D009010:Monte Carlo Method; D009154:Mutation; D010766:Phosphorylation; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism*; D012854:Sister Chromatid Exchange
chemical_list: C097151:Bloom syndrome protein; D053484:RecQ Helicases