TOPBP1 stabilizes BLM in S phase to inhibit sister chromatid exchange and genomic instability.

  • Major finding: TOPBP1 stabilizes BLM in S phase to inhibit sister chromatid exchange and genomic instability.

  • Mechanism: BLM is degraded by MIB1 in G1 phase, whereas TOBP1 interacts with phosphorylated BLM in S phase.

  • Impact: BLM downregulation in G1 phase limits end resection and promotes NHEJ-mediated DNA DSB repair.

Topoisomerase II binding protein 1 (TOPBP1) has been implicated as an important regulator of the DNA replication checkpoint and functions via interactions with DNA damage response proteins through its BRCA1 C terminus (BRCT) domains. Wang and colleagues found that TOPBP1 also interacts with Bloom syndrome helicase (BLM), a DNA helicase that suppresses aberrant sister chromatid exchange (SCE), promotes end resection–mediated repair of DNA double-strand breaks (DSB), and is mutated in Bloom syndrome, a disease characterized by growth defects and cancer predisposition. This interaction was cell-cycle regulated and dependent on the BRCT5 domain of TOPBP1 and phosphorylation of BLM at Ser338 by NIMA-related kinase 11 (NEK11) during S phase. Depletion of TOPBP1 significantly diminished BLM protein levels and augmented SCE, whereas reexpression of wild-type but not BRCT5-deficient TOPBP1 restored BLM expression and decreased SCE independent of the role of TOPBP1 in replication checkpoint control, suggesting that TOPBP1 prevents genomic instability by promoting BLM stability. Degradation of BLM was induced by mindbomb E3 ubiquitin protein ligase 1 (MIB1), which interacted with and polyubiquitinated BLM at N-terminal lysine residues specifically in G1 phase, and MIB1 depletion was sufficient to rescue the enhanced SCE phenotype in TOPBP1-deficient cells. In contrast, TOPBP1 binding to BLM in S phase blocked the interaction of BLM with MIB1 and suppressed MIB1-mediated BLM degradation. Intriguingly, expression of a nondegradable triple lysine mutant BLM protein resulted in reduced nonhomologous end joining (NHEJ) activity and decreased viability of cells exposed to radiation in G1 phase, suggesting that degradation of BLM in G1 inhibits end resection to facilitate NHEJ-driven DSB repair. Although additional studies are necessary to assess the role of MIB1-driven BLM degradation in tumorigenesis, these findings identify a role for TOPBP1-dependent suppression of SCE in the maintenance of genomic stability.

Wang J, Chen J, Gong Z. TopBP1 controls BLM protein level to maintain genome stability. Mol Cell 2013 Nov 14 [Epub ahead of print].