Nuclear-localized Asunder regulates cytoplasmic dynein localization via its role in the Integrator complex

Abstract

A pool of dynein anchored to the nuclear surface mediates many processes at G2/M, although its spatial and temporal regulation is poorly understood. Asunder, a critical regulator of dynein recruitment to the nuclear envelope, works in the nucleus as part of Integrator, an snRNA-processing complex, to mediate this event.

Lung function associated gene Integrator Complex subunit 12 regulates protein synthesis pathways

“…It remains unclear whether all INTScom subunits are required for some of these processes, especially that there is variability in the relative contributions of various complex members to snRNA processing [9–12], maintenance of perinuclear dynein [13] and ciliogenesis [17]. What remains to be elucidated is how INTScom perturbations yield specific yet diverse phenotypes.…”

“…It has been suggested that the primary mechanism behind that is the alteration of snRNA 3’-end formation affecting the splicing of mRNAs belonging to genes of particular functional groups explaining the specific phenotypic effects [13, 15, 16]. For instance, it has been argued that the induced downregulation of INTS5, INTS9, and INTS11 in zebrafish causes impaired haematopoiesis due to aberrant splicing of smad1 and smad5 via a dominant negative form of these transcripts [16].…”

“…For instance, it has been argued that the induced downregulation of INTS5, INTS9, and INTS11 in zebrafish causes impaired haematopoiesis due to aberrant splicing of smad1 and smad5 via a dominant negative form of these transcripts [16]. However, given the facts that INTS11 depletion results in a loss of perinuclear dynein whilst there was no enrichment for misprocessed transcripts encoding dynein-dynactin subunits, adaptor molecules or dynein-binding cassettes in HeLa cells [13] and our own observation of minor effect of INTS12 knockdown on snRNA processing concurrent with misbalanced protein synthesis, this hypothesis seems unlikely in a human model. This is further supported by a literature review of studies that compared the contribution of various INTScom members to snRNA processing, showing INTS12 to have a fairly small role in comparison to other members of the complex (Additional file 2: Table S6).…”

“…This complex was shown to stably accompany the C-terminal tail of RNA polymerase II (POLII) and at a molecular level has been implicated in small nuclear RNA (snRNA) biogenesis [9–12] dynein recruitment to the nuclear envelope at the mitotic onset [13] and with POLII pause and release [14]. At the physiological level, targeted knockdown and mutagenesis experiments demonstrated INTScom to be necessary for mouse adipogenesis [15], zebrafish haemopoiesis [16] as well as human primary ciliogenesis [17].…”

“…Drosophila ’s INTS12 was also implicated in the activation of a key heat shock response gene HSP70Aa [14]. In HeLa cells, INTS12 was specifically shown to be required for the maintenance of perinuclear dynein [13] and formation of primary cilia [17]. Although ciliogenesis is a dynein-dependent event [18, 19] it is thought that INTS12 is regulating these two processes separately from each other via the snRNA processing pathway [17].…”