Inner Nuclear Envelope Proteins SUN1 and SUN2 Play a Prominent Role in the DNA Damage Response

SummaryThe DNA damage response (DDR) and DNA repair are critical for maintaining genomic stability and evading many human diseases [1 and 2]. 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 [ 3 and 4]. 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 [ 2, 5 and 6]. 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.

► Sun1−/−Sun2−/− MEFs exhibited premature proliferative arrest at S phase ► Sun1−/−Sun2−/− MEFs exhibit excessive DNA damage ► DDR was impaired in Sun1−/−Sun2−/− MEFs ► SUN1 AND SUN2 interact with the DNAPK holoenzyme that plays a role in DDR