Northwestern University Feinberg School of Medicine

Daniel Foltz Lab

Centromere Licensing Through the Mis18 heterotetramer

The stable inheritance of vertebrate centromeres is an epigenetic process requiring deposition of new CENP-A nucleosomes by HJURP. New CENP-A nucleosomes are assembled in early G1 phase, immediately following mitosis. This process is turned on by the reduction in Cdk1 activity associated with exit from mitosis. Recently we have uncovered a process by which CENP-A nucleosome deposition is restricted to a single round per cell cycle. Mis18α and Mis18β form a heterotetramer through their C-terminal coiled-coil domains. HJURP is recruited to centromeres through a direct interaction between the HJURP centromere targeting domain and the Mis18α-β C-terminal coiled-coil domains. Mis18α-β heterotetramer formation is required for Mis18BP1 binding and centromere recognition. Interestingly, S. pombe contains a single Mis18 isoform that forms a homotetramer showing tetrameric Mis18 is conserved from fission yeast to humans. HJURP binding disrupts the Mis18α-β heterotetramer and removes Mis18α from centromeres.

We propose stable binding of Mis18 to centromeres in telophase licenses them for CENP-A deposition. Binding of HJURP deposits CENP-A at centromeres and facilitates the removal of Mis18, restricting CENP-A deposition to a single event per cell cycle. Going forward, we are interested in determining the molecular interactions that governs this self-limiting process.

Centromere Licensing