Mechanism of Bloom syndrome complex assembly required for double Holliday junction dissolution and genome stability

Author:

Hodson Charlotte1,Low Jason K. K.2ORCID,van Twest Sylvie1ORCID,Jones Samuel E.3ORCID,Swuec Paolo4,Murphy Vincent1ORCID,Tsukada Kaima35ORCID,Fawkes Matthew36,Bythell-Douglas Rohan17,Davies Adelina4,Holien Jessica K.789,O’Rourke Julienne J.1,Parker Benjamin L.2,Glaser Astrid1,Parker Michael W.910ORCID,Mackay Joel P.2ORCID,Blackford Andrew N.36ORCID,Costa Alessandro4ORCID,Deans Andrew J.17ORCID

Affiliation:

1. Genome Stability Unit, St. Vincent’s Institute of Medical Research, Fitzroy, VIC 3065, Australia

2. School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia

3. Department of Oncology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom

4. Francis Crick Institute, London NW1 1AT, United Kingdom

5. Laboratory for Zero-Carbon Energy, Institute of Innovative Research, Tokyo Institute of Technology, Tokyo 152-8550, Japan

6. MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom

7. Department of Medicine (St. Vincent’s), University of Melbourne, Fitzroy, VIC 3065, Australia

8. School of Science, RMIT University, Melbourne, VIC 3001, Australia

9. Structural Biology Unit, St. Vincent’s Institute of Medical Research, Fitzroy, VIC 3065, Australia

10. Bio21 Institute, University of Melbourne, Parkville, VIC 3010, Australia

Abstract

Significance Bloom syndrome complex (BS complex) is necessary for maintenance of genome stability and suppression of cancer-causing mutations. Composed of a helicase, a topoisomerase, and two scaffolds, the BS complex is implicated in several steps that ensure the high fidelity of DNA repair by recombination. One step, called “double Holliday junction dissolution,” ensures untangling of DNA at the conclusion of repair. Here, we used cross-link mass spectrometry to show how the BS complex assembles. Using biochemical reactions and cell complementation with mutant proteins, our results reveal an important role of helicase dimerization (and tight coupling of proteins within the complex) for double Holliday junction dissolution and genome stability.

Funder

Department of Health | National Health and Medical Research Council

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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