Abstract
Dynamic changes in microtubules during cell cycle progression are essential for spindle organization to ensure proper segregation of chromosomes. There is growing evidence that post translational modifications of tubulins are the key factors that contribute to microtubule dynamics. However, how dynamic properties of microtubules are regulated in mouse oocytes is unclear. Here, we show that tumor suppressor RASSF1A is required for tubulin acetylation by regulating SIRT2 and HDAC6 during meiotic maturation in mouse oocytes. We found that RASSF1A was localized at the spindle microtubules in mouse oocytes. Knockdown of RASSF1A perturbed meiotic progression by impairing spindle organization and chromosome alignment. Moreover, RASSF1A knockdown disrupted kinetochore-microtubule (kMT) attachment, which activated spindle assembly checkpoint and increased the incidence of aneuploidy. In addition, RASSF1A knockdown decreased tubulin acetylation by increasing SIRT2 and HDAC6 levels. Notably, defects in spindle organization and chromosome alignment after RASSF1A knockdown were rescued not only by inhibiting SIRT2 or HDAC6 activity, but also by overexpressing acetylation mimicking K40Q tubulin. Therefore, our results demonstrated that RASSF1A regulates SIRT2- and HDAC6-mediated tubulin acetylation for proper spindle organization during oocyte meiotic maturation.
Highlights
Microtubules are cylindrical cytoskeletal polymers composed of α/β-tubulin dimers and are implicated in a variety of cellular processes, including cellular transport, maintenance of cell structure, and spindle formation and chromosome segregation during cell division (Desai and Mitchison, 1997)
We found that Ras-association domain family 1A (RASSF1A) is localized at spindle microtubules and regulates spindle organization and chromosome segregation by modulating tubulin acetylation via SIRT2 and HDAC6 in mouse oocytes
Upon germinal vesicle (GV) breakdown (GVBD), as the chromatin was condensed into individual chromosomes, RASSF1A began to aggregate around the condensing chromosomes, simultaneous with the newly formed spindle microtubules
Summary
Microtubules are cylindrical cytoskeletal polymers composed of α/β-tubulin dimers and are implicated in a variety of cellular processes, including cellular transport, maintenance of cell structure, and spindle formation and chromosome segregation during cell division (Desai and Mitchison, 1997). Microtubules are highly dynamic by making a rapid change between growing and shrinking states. These dynamic properties are essential for various cellular functions, it remains unclear how microtubule dynamics are precisely controlled within cells. A growing body of evidence indicates that post-translational modifications of tubulins are key factors that contribute to microtubule dynamics (Magiera and Janke, 2014; Strzyz, 2016). Acetylation of lysine 40 (K40) of α-tubulin is one of the most-studied post-translational modifications that alters. Regulation of Tubulin Acetylation by RASSF1A the microtubule structure and affects the interactions between microtubules and microtubule-associated proteins (Sadoul and Khochbin, 2016). Precise knowledge of the physiological function of K40 acetylation in α-tubulin remains elusive
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