Fig. 7: A model of the centromere protection pathway.

a During chromosome alignment, CDK1 and PLK1 cooperate to promote multiple phosphorylation on different subunits of the ultrafine DNA bridge (UFB)-binding complexes, including BLM helicase and PICH DNA translocase. The inhibitory phosphorylation destabilises the assembly of the BTRR complex, RIF1-PP1s recruitment, limiting their association with PICH at kinetochore-associated (K)-chromatin in centromeres. The PLK1-mediated hyperphosphorylation on BLM also suppresses illegitimate DNA unwinding on centromeric DNA. Therefore, mitotic cells can maintain robust centromere structures to counteract bipolar spindle pulling forces and establish proper chromosome biorientation. b In the absence of PLK1 activity, the inhibition of BTRR/UFB-binding complexes is relieved in a RIF1-PP1s-dependent manner, resulting in illegitimate assembly of the BTRR/UFB-binding complexes at K-chromatin. The unleashing of BLM activity after the loss of PLK1-mediated phosphorylation leads to centromeric DNA unwinding as visualised by RPA binding and results in centromere disintegration (left). In the absence of RIF1-PP1s, this prevents efficient removal of the inhibitory phosphorylation by CDK1, limiting the initial assembly the BTRR/UFB-binding complexes at K-chromatin (right). c BLM phosphomutants lacking either serine 144 or the PLK1-mediated phosphorylation sites become dominantly active in centromeric DNA unwinding once the complexes assembly at K-chromatin is permitted after CDK1 inhibition.