A tri-serine cluster within the topoisomerase II alpha-interaction domain of the BLM helicase is required for regulating chromosome breakage in human cells

作者：Behnfeldt Julia Harris; Acharya Samir^*; Tangeman Larissa; Gocha April Sandy; Keirsey Jeremy; Groden Joanna^*

来源：Human Molecular Genetics, 2018, 27(7): 1241-1251.

DOI：10.1093/hmg/ddy038

The recQ-like helicase BLM interacts directly with topoisomerase II alpha to regulate chromosome breakage in human cells. We demonstrate that a phosphosite tri-serine cluster (S577/S579/S580) within the BLM topoisomerase II alpha-interaction region is required for this function. Enzymatic activities of BLM and topoisomerase IIa are reciprocally stimulated in vitro by ten-fold for topoisomerase IIa decatenation/relaxation activity and three-fold for BLM unwinding of forked DNA duplex substrates. A BLM transgene encoding alanine substitutions of the tri-serine cluster in BLM-/- transfected cells increases micronuclei, DNA double strand breaks and anaphase ultra-fine bridges (UFBs), and decreases cellular co-localization of BLM with topoisomerase IIa. In vitro, these substitutions significantly reduce the topoisomerase II alpha-mediated stimulation of BLM unwinding of forked DNA duplexes. Substitution of the tri-serine cluster with aspartic acids to mimic serine phosphorylation reverses these effects in vitro and in vivo. Our findings implicate the modification of this BLMtri-serine cluster in regulating chromosomal stability.

• 出版日期2018-4-1