Research in our lab is focused on understanding the molecular mechanisms that ensure error-free propagation of the genome during cell division, and how defects in these mechanisms contribute to chromosomal instability (CIN) in cancer cells. Research highlights include an explanation for how the duplicated chromosomes become attached to the opposite poles of the mitotic spindle, a prerequisite for faithful chromosome segregation. The chromosomal passenger complex (CPC) regulates chromosome-spindle connections by phosphorylation of substrates that mediate these attachments.
My group demonstrated how the non-enzymatic subunits of the CPC assist Aurora B, the core kinase of the complex, in reaching these substrates and provided compelling evidence for a direct role of the CPC in the function of the mitotic checkpoint, a surveillance mechanism that inhibits anaphase onset until all chromosomes are properly connected to the mitotic spindle. This finding challenged the prevailing idea that the mitotic checkpoint simply fails to be silenced because the CPC detaches microtubules from chromosomes when they do not connect the duplicated chromosomes to opposite spindle poles.
Furthermore, we were the first to generate a functional analog-sensitive Aurora B kinase mutant that allowed us to identify novel substrates of the CPC. When following up one of these substrates, Rif1 – a protein with a known function in DNA damage repair- we revealed a thus far unrecognized function for this protein in the resolution of ultrafine DNA bridges in anaphase that are formed by persistent DNA catanenes.
Together with our collaborators from PennU, we discovered how the CPC is able to discriminate between ‘right’ and ‘wrong’. Why does it sever error prone spindle-chromosome attachments, while it allows the stabilization of attachments that result in equal segregation? We provided experimental evidence for the model that upon chromosome bi-orientation, tension, generated by the opposing pulling forces of the connected microtubules, pulls substrates out of the sphere of influence of Aurora B kinase.
Our recent findings suggest a role for the non-enzymatic subunits of the CPC in cohesin stabilization at the centromere. Current research themes are the regulation of inner centromere integrity, the segregation behaviour of individual chromosomes, understanding how nuclear and cytoplasmic division are coordinated, and whether a deregulated CPC can explain chromosomal instability in cancer.