title: BLM protein mitigates formaldehyde-induced genomic instability.
abstract: Formaldehyde is a reactive aldehyde that has been classified as a class I human carcinogen by the International Agency for Cancer Research. There are growing concerns over the possible adverse health effects related to the occupational and environmental human exposures to formaldehyde. Although formaldehyde-induced DNA and protein adducts have been identified, the genomic instability mechanisms and the cellular tolerance pathways associated with formaldehyde exposure are not fully characterized. This study specifically examines the role of a genome stability protein, Bloom (BLM) in limiting formaldehyde-induced cellular and genetic abnormalities. Here, we show that in the absence of BLM protein, formaldehyde-treated cells exhibited increased cellular sensitivity, an immediate cell cycle arrest, and an accumulation of chromosome radial structures. In addition, live-cell imaging experiments demonstrated that formaldehyde-treated cells are dependent on BLM for timely segregation of daughter cells. Both wild-type and BLM-deficient formaldehyde-treated cells showed an accumulation of 53BP1 and γH2AX foci indicative of DNA double-strand breaks (DSBs); however, relative to wild-type cells, the BLM-deficient cells exhibited delayed repair of formaldehyde-induced DSBs. In response to formaldehyde exposure, we observed co-localization of 53BP1 and BLM foci at the DSB repair site, where ATM-dependent accumulation of formaldehyde-induced BLM foci occurred after the recruitment of 53BP1. Together, these findings highlight the significance of functional interactions among ATM, 53BP1, and BLM proteins as responders associated with the repair and tolerance mechanisms induced by formaldehyde.
authors.affiliation: Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR 97239 USA; Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239 USA.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Kumari
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239 USA.
authors.forename: Nichole
authors.initials: N
authors.lastname: Owen
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239 USA.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Juarez
authors.affiliation: Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR 97239 USA; Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239 USA. Electronic address: mcculloa@ohsu.edu.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: McCullough
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D005557:Formaldehyde / Q000633:toxicity*; D042822:Genomic Instability / Q000187:drug effects*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D053484:RecQ Helicases / Q000172:deficiency / Q000378:metabolism*; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D005557:Formaldehyde; D004247:DNA; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C097151:Bloom syndrome protein; D053484:RecQ Helicases
keywords: 53BP1; ATM; BLM; Double-strand breaks; Formaldehyde