Fellow: Miguel Angel Brieno-Enriquez

Mentor: Paula E. Cohen

DESCRIPTION (provided by applicant): 

Meiosis is a specialized cell division characterized by a single round of DNA replication followed by two rounds of chromosome segregation, resulting in the formation of gametes. Cohesin is a chromosome-associated multiprotein ring that maintains sister chromatid cohesion, and which is essential for accurate chromosome/chromatid segregation. During meiosis, cohesin disassembly is particularly complicated by the requirement for sequential loss of cohesion along the chromosome arms at the first meiotic division (MI) and then at the centromere during the second meiotic division (MII). NIMA-like kinase 1 (NEK1) is a dual specific serine/threonine and tyrosine kinase that is highly expressed in germ cells. Loss of NEK1 in mice leads to retention of the cohesin subunit SMC3 on chromosome arms at MI and subsequent infertility. Cohesin removal is orchestrated in two steps, first by “the prophase pathway”, followed by Separase-mediated cleavage of the cohesin ring. The prophase pathway is defined by the stoichiometry between the Wings-apart-like protein (WAPL) and Sororin, which compete for binding to PDS5B on the cohesin ring, but this pathway has not yet been described in meiosis. My preliminary data reveal exciting roles for NEK1 in the regulation of cohesin dynamics at MI, both directly at the level of the cohesin subunits, SMC3, RAD21L and REC8, and indirectly through phosphorylation the PDS5B-WAPL complex. Furthermore, my studies have shown that NEK1 action on the prophase pathway is mediated via Protein Phosphatase 1-gamma (PP1γ), which is a phosphotarget of NEK1, and which binds and de-phoshphorylates WAPL. Moreover, my preliminary studies indicate that NEK1 also regulates a cascade of other NEK proteins to perform other roles in MI that are distinct from its activity on cohesion dynamics. Thus, I hypothesize that NEK1 acts as master regulator of events in meiosis, primarily playing a crucial role in the timing of cohesin removal at MI through its actions on critical components of the prophase pathway, but also in orchestrating the actions of other NEK kinases. My long term goal is to elucidate how NEK1 regulates cohesion removal at MI, but also to further characterize the role of NEK1 catalytic activity in orchestrating downstream events at both meiotic divisions. Three specific aims are proposed: (1) To elucidate the role of NEK1 in the phosphorylation of PP1γ, (2) To assess the importance of WAPL phosphorylation on cohesion removal at MI and (3) To elucidate the function of NEK1 as a master regulator of the NEK family during meiosis. These experiments will provide a novel and exciting data that describes, for the first time, the the role of NEK1 in the regulation of cohesin removal during the prophase pathway in meiosis.