An Aurora kinase A-BOD1L1-PP2A B56 Axis promotes chromosome segregation fidelity

Cancer cells are often aneuploid and frequently display elevated rates of chromosome mis-segregation, called chromosomal instability (CIN). CIN is caused by hyperstable kinetochore-microtubule (K-MT) attachments that reduce the correction efficiency of erroneous K-MT attachments. UMK57, a chemical agonist of the protein MCAK improves chromosome segregation fidelity in CIN cancer cells by destabilizing K-MT attachments, but cells rapidly develop resistance. To determine the mechanism, we performed unbiased screens which revealed increased phosphorylation in cells adapted to UMK57 at Aurora kinase A phosphoacceptor sites on BOD1L1. BOD1L1 depletion or Aurora kinase A inhibition eliminated resistance to UMK57. BOD1L1 localizes to spindles/kinetochores during mitosis, interacts with the PP2A phosphatase, and regulates phosphorylation levels of kinetochore proteins, chromosome alignment, mitotic progression and fidelity. Moreover, the BOD1L1 gene is mutated in a subset of human cancers, and BOD1L1 depletion reduces cell growth in combination with clinically relevant doses of taxol or Aurora kinase A inhibitor.

癌细胞通常为非整倍体细胞，且常表现出升高的染色体错分离速率，该现象被称为染色体不稳定性（chromosomal instability, CIN）。CIN由过度稳定的动粒-微管（kinetochore-microtubule, K-MT）连接引发，此类连接会降低错误K-MT连接的纠错效率。UMK57是蛋白MCAK（MCAK）的化学激动剂，可通过破坏K-MT连接的稳定性，提升CIN阳性癌细胞的染色体分离保真度，但癌细胞会快速产生耐药性。为阐明该耐药性的分子机制，我们开展了无偏筛选实验，结果发现，在适应UMK57处理的细胞中，BOD1L1上的极光激酶A（Aurora kinase A）磷酸接受位点的磷酸化水平显著升高。后续实验证实，敲低BOD1L1或抑制极光激酶A，均可消除细胞对UMK57的耐药性。BOD1L1在有丝分裂过程中定位于纺锤体/动粒，可与PP2A磷酸酶（PP2A phosphatase）相互作用，并调控动粒蛋白的磷酸化水平、染色体列队、有丝分裂进程及分离保真度。此外，BOD1L1基因在部分人类癌症中存在突变；且在联合应用临床相关剂量的紫杉醇（taxol）或极光激酶抑制剂时，敲低BOD1L1可抑制细胞生长。