title: Snm1B/Apollo functions in the Fanconi anemia pathway in response to DNA interstrand crosslinks.
abstract: Fanconi anemia (FA) is an inherited chromosomal instability disorder characterized by childhood aplastic anemia, developmental abnormalities and cancer predisposition. One of the hallmark phenotypes of FA is cellular hypersensitivity to agents that induce DNA interstrand crosslinks (ICLs), such as mitomycin C (MMC). FA is caused by mutation in at least 14 genes which function in the resolution of ICLs during replication. The FA proteins act within the context of a protein network in coordination with multiple repair factors that function in distinct pathways. SNM1B/Apollo is a member of metallo-β-lactamase/βCASP family of nucleases and has been demonstrated to function in ICL repair. However, the relationship between SNM1B and the FA protein network is not known. In the current study, we establish that SNM1B functions epistatically to the central FA factor, FANCD2, in cellular survival after ICL damage and homology-directed repair of DNA double-strand breaks. We also demonstrate that MMC-induced chromosomal anomalies are increased in SNM1B-depleted cells, and this phenotype is not further exacerbated upon depletion of either FANCD2 or another key FA protein, FANCI. Furthermore, we find that SNM1B is required for proper localization of critical repair factors, including FANCD2, BRCA1 and RAD51, to MMC-induced subnuclear foci. Our findings demonstrate that SNM1B functions within the FA pathway during the repair of ICL damage.
authors.affiliation: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Mason
authors.forename: JoAnn M
authors.initials: JM
authors.lastname: Sekiguchi
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology; D043171:Chromosomal Instability / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D005090:Exodeoxyribonucleases; D005199:Fanconi Anemia / Q000201:enzymology* / Q000235:genetics; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000477:Alkylating Agents; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins; D016685:Mitomycin; C493741:DCLRE1B protein, human; D005090:Exodeoxyribonucleases; D045643:DNA Repair Enzymes