@article {90598, title = {Antagonistic roles for Ataxin-2 structured and disordered domains in RNP condensation.}, journal = {Elife}, volume = {10}, year = {2021}, month = {2021 Mar 10}, abstract = {

Ataxin-2 (Atx2) is a translational control molecule mutated in spinocerebellar ataxia type II and amyotrophic lateral sclerosis. While intrinsically disordered domains (IDRs) of Atx2 facilitate mRNP condensation into granules, how IDRs work with structured domains to enable positive and negative regulation of target mRNAs remains unclear. Using the Targets of RNA-Binding Proteins Identified by Editing technology, we identified an extensive data set of Atx2-target mRNAs in the brain and S2 cells. Atx2 interactions with AU-rich elements in 3{\textquoteright}UTRs appear to modulate stability/turnover of a large fraction of these target mRNAs. Further genomic and cell biological analyses of Atx2 domain deletions demonstrate that Atx2 (1) interacts closely with target mRNAs within mRNP granules, (2) contains distinct protein domains that drive or oppose RNP-granule assembly, and (3) has additional essential roles outside of mRNP granules. These findings increase the understanding of neuronal translational control mechanisms and inform strategies for Atx2-based interventions under development for neurodegenerative disease.

}, issn = {2050-084X}, doi = {10.7554/eLife.60326}, author = {Singh, Amanjot and Hulsmeier, Joern and Kandi, Arvind Reddy and Pothapragada, Sai Shruti and Hillebrand, Jens and Petrauskas, Arnas and Agrawal, Khushboo and Rt, Krishnan and Thiagarajan, Devasena and Jayaprakashappa, Deepa and VijayRaghavan, K and Ramaswami, Mani and Bakthavachalu, Baskar} } @article {62775, title = {Adult Drosophila muscle morphometry through microCT reveals dynamics during ageing.}, journal = {Open Biol}, volume = {9}, year = {2019}, month = {2019 Jun 28}, pages = {190087}, abstract = {

Indirect flight muscles (IFMs) in adult Drosophila provide the key power stroke for wing beating. They also serve as a valuable model for studying muscle development. An age-dependent decline in Drosophila free flight has been documented, but its relation to gross muscle structure has not yet been explored satisfactorily. Such analyses are impeded by conventional histological preparations and imaging techniques that limit exact morphometry of flight muscles. In this study, we employ microCT scanning on a tissue preparation that retains muscle morphology under homeostatic conditions. Focusing on a subset of IFMs called the dorsal longitudinal muscles (DLMs), we find that DLM volumes increase with age, partially due to the increased separation between myofibrillar fascicles, in a sex-dependent manner. We have uncovered and quantified asymmetry in the size of these muscles on either side of the longitudinal midline. Measurements of this resolution and scale make substantive studies that test the connection between form and function possible. We also demonstrate the application of this method to other insect species making it a valuable tool for histological analysis of insect biodiversity.

}, issn = {2046-2441}, doi = {10.1098/rsob.190087}, author = {Chaturvedi, Dhananjay and Prabhakar, Sunil and Aggarwal, Aman and Atreya, Krishan B and VijayRaghavan, K} } @article {55792, title = {Asrij/OCIAD1 suppresses CSN5-mediated p53 degradation and maintains mouse hematopoietic stem cell quiescence.}, journal = {Blood}, year = {2019}, month = {2019 Apr 05}, abstract = {

Inactivation of the tumor suppressor p53 is essential for unrestrained growth of cancers. However, only 11\% of hematological malignancies have mutant p53. Mechanisms that cause wild type p53 dysfunction and promote leukemia are inadequately deciphered. The stem cell protein Asrij/OCIAD1 is misexpressed in several human hematological malignancies and implicated in the p53 pathway and DNA damage response. However, Asrij function in vertebrate hematopoiesis remains unknown. We generated the first asrij null (knockout, KO) mice and show that they are viable and fertile with no gross abnormalities. However, by six months, they exhibit increased peripheral blood cell counts, splenomegaly and an expansion of bone marrow hematopoietic stem cells (HSCs) with higher myeloid output. HSCs lacking Asrij are less quiescent and more proliferative with higher repopulation potential as observed from serial transplantation studies. However, stressing KO mice with sub-lethal gamma irradiation or multiple injections of 5-fluorouracil results in reduced survival and rapid depletion of hematopoietic stem/progenitor cells (HSPCs) by driving them into proliferative exhaustion. Molecular and biochemical analyses revealed increased polyubiquitinated protein levels, Akt/STAT5 activation and CSN5 (COP9 signalosome subunit 5)-mediated p53 ubiquitination and degradation in KO HSPCs. Further, we show that Asrij sequesters CSN5 via its conserved OCIA domain, thereby preventing p53 degradation. In agreement, Nutlin-3 treatment of KO mice restored p53 levels and reduced high HSPC frequencies. Thus, we provide a new mouse model resembling myeloproliferative disease and identify a post-translational regulator of wild type p53 essential for maintaining HSC quiescence that could be a potential target for pharmacological intervention.

}, issn = {1528-0020}, doi = {10.1182/blood.2019000530}, author = {Sinha, Saloni and Dwivedi, Tirath Raj and Yengkhom, Roja and Bheemsetty, Venkata Anudeep and Abe, Takaya and Kiyonari, Hiroshi and VijayRaghavan, K and Inamdar, Maneesha S} }