title: Stabilization and targeting of INO80 to replication forks by BAP1 during normal DNA synthesis.
abstract: The INO80 chromatin-remodelling complex has been implicated in DNA replication during stress in yeast. However, its role in normal DNA replication and its underlying mechanisms remain unclear. Here, we show that INO80 binds to replication forks and promotes fork progression in human cells under unperturbed, normal conditions. We find that Ino80, which encodes the catalytic ATPase of INO80, is essential for mouse embryonic DNA replication and development. Ino80 is recruited to replication forks through interaction with ubiquitinated H2A--aided by BRCA1-associated protein-1 (BAP1), a tumour suppressor and nuclear de-ubiquitinating enzyme that also functions to stabilize Ino80. Importantly, Ino80 is downregulated in BAP1-defective cancer cells due to the lack of an Ino80 stabilization mechanism via BAP1. Our results establish a role for INO80 in normal DNA replication and uncover a mechanism by which this remodeler is targeted to replication forks, suggesting a molecular basis for the tumour-suppressing function of BAP1.
authors.affiliation: Department of Life Science, The Research Center for Cellular Homeostasis, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 120-750, Korea.
authors.forename: Han-Sae
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Department of Life Science, The Research Center for Cellular Homeostasis, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 120-750, Korea.
authors.forename: Shin-Ai
authors.initials: SA
authors.lastname: Lee
authors.affiliation: Department of Life Science, The Research Center for Cellular Homeostasis, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 120-750, Korea.
authors.forename: Shin-Kyoung
authors.initials: SK
authors.lastname: Hur
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea.
authors.forename: Jeong-Wook
authors.initials: JW
authors.lastname: Seo
authors.affiliation: Department of Life Science, The Research Center for Cellular Homeostasis, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 120-750, Korea.
authors.forename: Jongbum
authors.initials: J
authors.lastname: Kwon
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D004265:DNA Helicases / Q000378:metabolism*; D004261:DNA Replication; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D005091:Exons; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000378:metabolism*; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000737:chemistry; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*
chemical_list: C400134:BAP1 protein, human; C575444:BAP1 protein, mouse; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D043222:Ubiquitin Thiolesterase; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities; D004265:DNA Helicases; C524421:INO80 protein, human; C000603449:INO80 protein, mouse