Chromosome instability (CIN), recognized as a hallmark of several cancers, results from error in chromosome segregation leading to differences in both chromosome structure and numbers. Chromosome Segregation protein (CSE4) in budding yeast and CENP-A in humans are examples of an evolutionary conserved histone H3 variant in all eukaryotic centromeres which have a crucial role in efficient chromosome segregation. As such, overexpression of CSE4 (or CENP-A) are known to cause mislocalization of the protein to non-centromeric chromatin leading to CIN.
In an interesting study in Nucleic Acids Research, Ohkuni et al. have shown how mislocalized Cse4p is removed and targeted for proteasomal degradation, thus preventing CIN. The authors show that Cdc48p-Npl4p-Ufd1p AAA ATPase complex recognizes the mislocalized and polyubiquinated Cse4p and facilitates its removal from the non-centromeric chromatin, targeting it for degradation. The authors demonstrate that the Cdc48p complex targets specifically the mislocalized chromatin-bound Cse4p and not the centromeric Cse4p. Another essential factor involved in this mechanism is an E3 ubiquitin ligase, Psh1p, which polyubiquinates Cse4p and promotes its recognition by Cdc48p-Npl4p-Ufd1p AAA ATPase complex via its cofactor Npl4p.
This paper demonstrates an important role for the Cdc48-Npl4-Ufd1 AAA ATPase complex in removing mislocalized Cse4p from non-centromeric chromatin. It infers that accumulation of mislocalized CENP-A may contribute to aneuploidy in human cancers, thus revealing another pathway to target for treating human diseases.