A tri-serine cluster within the topoisomerase IIα-interaction domain of the BLM helicase is required for regulating chromosome breakage in human cells
| Autor: | Larissa Tangeman, Jeremy Keirsey, Samir Acharya, Joanna Groden, April Renee Sandy Gocha, Julia Harris Behnfeldt |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
congenital hereditary and neonatal diseases and abnormalities Biology Cell Line Serine 03 medical and health sciences chemistry.chemical_compound Protein Domains Chromosomal Instability Genetics Humans Poly-ADP-Ribose Binding Proteins Molecular Biology Genetics (clinical) Anaphase RecQ Helicases urogenital system Topoisomerase nutritional and metabolic diseases Helicase Chromosome Breakage Articles General Medicine Transfection Cell biology DNA Topoisomerases Type II 030104 developmental biology chemistry biology.protein Phosphorylation Chromosome breakage DNA |
| Zdroj: | Human Molecular Genetics. 27:1241-1251 |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddy038 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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