A tri-serine cluster within the topoisomerase II?-interaction domain of the BLM helicase is required for regulating chromosome breakage in human cells.
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ABSTRACT: The recQ-like helicase BLM interacts directly with topoisomerase II? to regulate chromosome breakage in human cells. We demonstrate that a phosphosite tri-serine cluster (S577/S579/S580) within the BLM topoisomerase II?-interaction region is required for this function. Enzymatic activities of BLM and topoisomerase II? are reciprocally stimulated in vitro by ten-fold for topoisomerase II? 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 II?. In vitro, these substitutions significantly reduce the topoisomerase II?-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 BLM tri-serine cluster in regulating chromosomal stability.
SUBMITTER: Behnfeldt JH
PROVIDER: S-EPMC6159539 | biostudies-literature | 2018 Apr
REPOSITORIES: biostudies-literature
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