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.
Highlights
Bloom syndrome (BS) is a very rare genetic disorder with features of significant growth deficiency, hypo- and hyperpigmented skin, sun-sensitive facial skin lesions, cancer predisposition in early life and male infertility [1,2]
Bloom syndrome is an example of a genome instability disorder where cells cannot efficiently untangle DNA after replication
We describe two affected individuals with Bloom-like features with a homozygous deletion of the RMI2 gene
Summary
Bloom syndrome (BS) is a very rare genetic disorder with features of significant growth deficiency, hypo- and hyperpigmented skin, sun-sensitive facial skin lesions, cancer predisposition in early life and male infertility [1,2]. Protein interaction studies have shown that the BLM protein is a member of a four-subunit complex that includes topoisomerase III alpha (TOP3A) [5,6] and RecQ-mediated genome instability proteins 1 [7,8,9] and 2 [10,11] (RMI1 & 2), collectively known as the BTR complex. The BTR complex has been proposed to localise to stalled replication forks via interactions with Fanconi anaemia (FANC) subunits and Replication Protein A [20]. Similar to BS, Fanconi anemia patients exhibit growth deficiencies, chromosomal breaks, heightened genomic instability and cancer predisposition [21]. Further evidence to support this connection is through structural analyses with a FANCM peptide and the RMI1-RMI2 heterodimer [22]
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