TopBP1 Controls BLM Protein Level to Maintain Genome Stability

Human TopBP1 is a key mediator protein involved in DNA replication checkpoint control. In this study, we report a specific interaction between TopBP1 and Bloom syndrome helicase (BLM) that is phosphorylaton and cell-cycle dependent. Interestingly, TopBP1 depletion led to decreased BLM protein level and increased sister chromatid exchange (SCE). Moreover, our data indicated that BLM was ubiquitinated by E3 ligase MIB1 and degraded in G1 cells but was stabilized by TopBP1 in S phase cells. Depletion of MIB1 restored BLM protein level and rescued the elevated SCE phenotype in TopBP1-depleted cells. In addition, cells expressing an undegradable BLM mutant showed radiation sensitivity, probably by triggering end resection and inhibiting the nonhomologous end-joining (NHEJ) pathway in G1 phase. Altogether, these data suggest that, although BLM is downregulated in G1 phase in order to promote NHEJ-mediated DNA repair, it is stabilized by TopBP1 in S phase cells in order to suppress SCE and thereby prevent genomic instability.