Chk1 protects against chromatin bridges by constitutively phosphorylating BLM serine 502 to inhibit BLM degradation

Chromatin bridges represent incompletely segregated chromosomal DNA connecting the anaphase poles and can result in chromosome breakage. The Bloom's syndrome protein (BLM) helicase suppresses formation of chromatin bridges. Here, we show that checkpoint kinase 1 (Chk1)-deficient cells exhibit higher frequency of chromatin bridges and reduced BLM protein levels compared to controls. Chk1-inhibition leads to BLM ubiquitination and proteasomal degradation in interphase. Furthermore, Chk1 constitutively phosphorylates human BLM at serine 502 (S502) and phosphorylated BLM localises to chromatin bridges. Non-phosphorylatable mutation of S502 to alanine (S502A) reduces stability of BLM protein whereas expression of a phospho-mimicking S502D BLM, in which S502 is mutated to aspartic acid, stabilises BLM and prevents chromatin bridges in Chk1-deficient cells. In addition, wild-type but not S502D BLM associates with Cullin 3 and Cullin 3-depletion rescues BLM accumulation and localisation to chromatin bridges after Chk1-inhibition. We propose that Chk1 phosphorylates BLM-S502 to inhibit Cullin 3-mediated BLM degradation in interphase. These results suggest that Chk1 prevents deleterious anaphase bridges by stabilising BLM.