title: Inner nuclear envelope proteins SUN1 and SUN2 play a prominent role in the DNA damage response.
abstract: The DNA damage response (DDR) and DNA repair are critical for maintaining genomic stability and evading many human diseases. Recent findings indicate that accumulation of SUN1, a nuclear envelope (NE) protein, is a significant pathogenic event in Emery-Dreifuss muscular dystrophy and Hutchinson-Gilford progeria syndrome, both caused by mutations in LMNA. However, roles of mammalian SUN proteins in mitotic cell division and genomic stability are unknown. Here we report that the inner NE proteins SUN1 and SUN2 may play a redundant role in DDR. Mouse embryonic fibroblasts from Sun1(-/-)Sun2(-/-) mice displayed premature proliferation arrest in S phase of cell cycle, increased apoptosis and DNA damage, and decreased perinuclear heterochromatin, indicating genome instability. Furthermore, activation of ATM and H2A.X, early events in DDR, were impaired in Sun1(-/-)Sun2(-/-) fibroblasts. A biochemical screen identified interactions between SUN1 and SUN2 and DNA-dependent protein kinase (DNAPK) complex that functions in DNA nonhomologous end joining repair and possibly in DDR. Knockdown of DNAPK reduced ATM activation in NIH 3T3 cells, consistent with a potential role of SUN1- and SUN2-DNAPK interaction during DDR. SUN1 and SUN2 could affect DDR by localizing certain nuclear factors to the NE or by mediating communication between nuclear and cytoplasmic events.
authors.affiliation: Institute of Developmental Biology and Molecular Medicine, School of Life Science, Fudan University, Shanghai 200433, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Lei
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Zhu
authors.forename: Rener
authors.initials: R
authors.lastname: Xu
authors.forename: Chunlin
authors.initials: C
authors.lastname: Shao
authors.forename: Tian
authors.initials: T
authors.lastname: Xu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhuang
authors.forename: Min
authors.initials: M
authors.lastname: Han
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D042822:Genomic Instability; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; C464932:SUN1 protein, mouse; C520338:Sun2 protein, mouse; D034501:Telomere-Binding Proteins; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse