Loss of RMI2 Increases Genome Instability and Causes a Bloom-Like Syndrome

Damien F Hudson; David J Amor; Amber Boys; Kathy Butler; Lorna Williams; Tao Zhang; Paul Kalitsis

doi:10.1371/journal.pgen.1006483

Loss of RMI2 Increases Genome Instability and Causes a Bloom-Like Syndrome

PLoS Genet. 2016 Dec 15;12(12):e1006483. doi: 10.1371/journal.pgen.1006483. eCollection 2016 Dec.

Authors

Damien F Hudson^{1

2}, David J Amor^{1

2}, Amber Boys³, Kathy Butler³, Lorna Williams³, Tao Zhang^{1

2}, Paul Kalitsis^{1

2}

Affiliations

¹ Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Parkville, Victoria, Australia.
² Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
³ Cytogenetics Laboratory, Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Parkville, Victoria, Australia.

Abstract

Bloom syndrome is a recessive human genetic disorder with features of genome instability, growth deficiency and predisposition to cancer. The only known causative gene is the BLM helicase that is a member of a protein complex along with topoisomerase III alpha, RMI1 and 2, which maintains replication fork stability and dissolves double Holliday junctions to prevent genome instability. Here we report the identification of a second gene, RMI2, that is deleted in affected siblings with Bloom-like features. Cells from homozygous individuals exhibit elevated rates of sister chromatid exchange, anaphase DNA bridges and micronuclei. Similar genome and chromosome instability phenotypes are observed in independently derived RMI2 knockout cells. In both patient and knockout cell lines reduced localisation of BLM to ultra fine DNA bridges and FANCD2 at foci linking bridges are observed. Overall, loss of RMI2 produces a partially active BLM complex with mild features of Bloom syndrome.

MeSH terms

Bloom Syndrome / complications
Bloom Syndrome / genetics*
Bloom Syndrome / pathology
Chromosomal Instability / genetics
DNA Helicases / genetics
DNA, Cruciform / genetics
DNA-Binding Proteins / genetics*
Fanconi Anemia Complementation Group D2 Protein / genetics*
Genetic Predisposition to Disease
Genomic Instability
Humans
Multiprotein Complexes / genetics
Neoplasms / complications
Neoplasms / genetics*
Neoplasms / pathology
Nuclear Proteins / genetics*
Sister Chromatid Exchange / genetics

Substances

DNA, Cruciform
DNA-Binding Proteins
FANCD2 protein, human
Fanconi Anemia Complementation Group D2 Protein
Multiprotein Complexes
Nuclear Proteins
RMI2 protein, human
DNA Helicases

Grants and funding

This work was supported by National Health and Medical Research Council (nhmrc.gov.au) Australia Project Grants GNT1069223, GNT1030358 and GNT1047009 and the Victorian Government’s Operational Infrastructure Support Program (vic.gov.au). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.