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A3: The role of non-canonical poly(A) polymerases in regulating germ cell homeostasis

Supervisor: Dr. Christian Eckmann  

Specific aim(s)/topic(s) 

(1) The role of GLD-4 in promoting germline stem cell self-renewal

(2) The role of GLD-4 and GLD-2 in promoting meiotic commitment

 

Background and significance

Our broad goal is to understand animal tissue development and pathology at the level of cytoplasmic gene expression regulation. We are particularly interested in the function of non-canonical poly(A) polymerases that modify mRNA molecules at their 3’ends and thereby control biological processes as diverse as cellular senescence, stress response, and gametogenesis 26.

Cytoplasmic poly(A) polymerases (cytoPAPs) are crucial regulators of post-transcriptional mRNA control and evolutionary conserved across metazoans. In contrast to canonical PAP, which generally localizes to the nucleus and associates with mRNA targets via an intrinsic RRM-type fold, cytoPAPs lack a similar region of conservation and possess no predictable RNA-binding domains. While canonical PAP polyadenylates mRNA precursors, cytoPAPs are proposed to be more specific in targeting mature RNAs. Together this suggests the existence of RNA-adaptor proteins that specifically recruit cytoPAPs to their target mRNAs; however, few RNA-adaptors and target mRNAs are known to date. Moreover, whereas canonical PAP is a very active enzyme in vitro, cytoPAPs are by themself very inefficient enzymes that display increased polyadenylation activity in the presence of additional protein cofactors, suggesting that cytoPAPs themselves might be highly regulated enzymes and part of larger ribonucleoprotein particles (mRNPs) controlling mRNA fates. Importantly, germ cell development relies heavily on cytoPAP function and its absence leads to sterility. The pleiotropy of the germ cell defects suggests that cytoPAPs promote the efficient translation of mRNAs that encode cell fate establishment and maintenance factors.