Tom Meier Lab



Our group is studying the mechanism and regulation of nucleolar ribonucleoprotein biogenesis in relation to nuclear dynamics, genetic disease, and human reproduction. Presently we are pursuing two main areas of research:

First, we are analyzing the biogenesis and function of small nucleolar ribonucleoproteins (snoRNPs) of the H/ACA class and how minor deviations from their natural assembly pathway can lead to cancer and bone marrow failure. Human H/ACA ribonucleoproteins are important for many basic cellular processes including protein synthesis, pre-mRNA splicing, and genome integrity. The different functional classes of H/ACA RNPs isomerize some 130 uridines to pseudouridines in ribosomal (r) and spliceosomal small nuclear (sn) RNAs, process rRNA, stabilize telomerase RNA, yield microRNAs, and harbor yet to be determined roles. Each of these functions is specified by one of over 150 H/ACA RNAs, each of which associates with the same four core proteins to form an H/ACA RNP. The central core protein, NAP57 (aka dyskerin or in yeast Cbf5p), is mutated in the predominant X-linked form of the inherited bone marrow failure syndrome dyskeratosis congenita (DC). NAP57 was recently implicated as an oncogenic protein together with the RNP assembly chaperones pontin and reptin, whereas the H/ACA RNP-specific assembly factor SHQ1 is a tumor suppressor of prostate and other cancers. We identify how oncogenic point mutations in these proteins perturb H/ACA RNP assembly and how it can lead to an imbalance in cellular protein expression and genome instability. For this purpose, we are collaborating with structural biologists and clinical scientists. 

Second, we investigate the function of nucleolar channel systems (NCSs) in the cell and in human reproduction. During the height of receptivity of each menstrual cycle, NCSs transiently develop in the nuclei of endometrial epithelial cells (EECs). They are implicated in the preparation of the endometrium for uterine attachment of the fertilized egg. Although the molecular mechanisms of embryo implantation in humans are poorly understood, NCSs remain unexplored as candidate markers or potential prerequisites for implantation. This can be attributed to the fact that, despite their discovery over 50 years ago, identification of NCSs is still limited to electron microscopy. We identified a molecular marker of the NCS, the monoclonal antibody mAb414 against nuclear pore complex proteins (nucleoporins), which for the first time allows simple and robust detection of these organelles at the light microscopic level. We are now exploiting our discovery to understand the cellular biology of NCSs and their regulation and function in uterine biology. The latter should have broad applicability to fertility, its regulation, and cancer.

Students are welcome to choose between the two major and the many smaller projects currently ongoing in the laboratory.

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