A Tri-serine Cluster Within the Topoisomerase IIα-interaction Domain of the BLM Helicase is Required for Regulating Chromosome Breakage in Human Cells

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2018 Feb 1

PMID 29385443

Citations 2

Authors

Julia Harris Behnfeldt

Samir Acharya

Larissa Tangeman

April Sandy Gocha

Jeremy Keirsey

Joanna Groden

Affiliations

Soon will be listed here.

Abstract

The recQ-like helicase BLM interacts directly with topoisomerase IIα to regulate chromosome breakage in human cells. We demonstrate that a phosphosite tri-serine cluster (S577/S579/S580) within the BLM topoisomerase IIα-interaction region is required for this function. Enzymatic activities of BLM and topoisomerase IIα are reciprocally stimulated in vitro by ten-fold for topoisomerase IIα 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 IIα. In vitro, these substitutions significantly reduce the topoisomerase IIα-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.

Citing Articles

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