The role of polo-like kinase 4 (PLK4) in chromosome segregation and genome maintenance in mammalian meiosis

Meiosis;PLK4;spermatogenesis;Cell Biology

Jamabo, MiebakaJordan, Philip ;

Johns Hopkins University

关键词: Meiosis;    PLK4;    spermatogenesis;    Cell Biology;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/39471/JAMABO-THESIS-2016.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Polo-like kinase 4 (PLK4) belongs to the family of polo-like kinases (PLK1-5), an evolutionarily conserved family of serine/threonine kinases containing a characteristic polo box and similar architecture. PLK4 differs from the other polo-like kinases by possessing a structurally divergent sequence and therefore different substrate specificity and mechanism of action. Previous studies of PLK4 have centered on its role in centriole biogenesis. Overexpression of PLK4 has been shown to cause centrosome amplification and supernumerary centrosomes are a signature event in tumorigenesis and cancer. Recently, PLK4 has been implicated in the process of spermatogenesis. Mutation within the kinase domain of PLK4 was found to cause hypogonadism and germ cell loss. Our lab also reported that PLK4 localizes to the largely unsynapsed X and Y axes during meiotic prophase I, displaying a similar pattern to proteins involved in the process of meiotic sex chromosome inactivation (MSCI). These findings suggests that PLK4 harbors a novel role in MSCI during spermatogenesis and aberrancies in PLK4 function leads to meiotic arrest, loss of germ cells and infertility. Using the potent and reversible small molecule inhibitor of PLK4, centrinone as well as mutant mice bearing a mutation in the kinase domain of PLK4, we assess the progression of meiosis to check for defects specifically at prophase I stage while comparing the observations to their wild type littermates. Our data exhibits delays in meiotic progression as well as an indicating misregulation of DNA damage response in centrinone treated cells. Based on existing literature as well as findings from this study, we present strong evidence that the protein PLK4 has a role to play in accurate chromosome segregation and MSCI during prophase I of male meiosis. Inhibition or mutation of PLK4 results in meiotic failure which eventually leads to apoptosis and loss of germ cells. The mechanistic details and full repertoire of proteins and their substrates involved in this process is still being studied and we propose PLK4 as a key player in MSCI and spermatogenesis.