Bloom syndrome radials are predominantly non-homologous and are suppressed by phosphorylated BLM

Nichole Owen, James Hejna, Scott Rennie, Asia Mitchell, Amy Hanlon Newell, Navid Ziaie, Robb E. Moses, Susan B. Olson

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Biallelic mutations in BLM cause Bloom syndrome (BS), a genome instability disorder characterized by growth retardation, sun sensitivity and a predisposition to cancer. As evidence of decreased genome stability, BS cells demonstrate not only elevated levels of spontaneous sister chromatid exchanges (SCEs), but also exhibit chromosomal radial formation. The molecular nature and mechanism of radial formation is not known, but radials have been thought to be DNA recombination intermediates between homologs that failed to resolve. However, we find that radials in BS cells occur over 95% between non-homologous chromosomes, and occur non-randomly throughout the genome. BLM must be phosphorylated at T99 and T122 for certain cell cycle checkpoints, but it is not known whether these modifications are necessary to suppress radial formation. We find that exogenous BLM constructs preventing phosphorylation at T99 and T122 are not able to suppress radial formation in BS cells, but are able to inhibit SCE formation. These findings indicate that BLM functions in 2 distinct pathways requiring different modifications. In one pathway, for which the phosphorylation marks appear dispensable, BLM functions to suppress SCE formation. In a second pathway, T99 and T122 phosphorylations are essential for suppression of chromosomal radial formation, both those formed spontaneously and those formed following interstrand crosslink damage.

Original languageEnglish (US)
Pages (from-to)255-263
Number of pages9
JournalCytogenetic and Genome Research
Volume144
Issue number4
DOIs
StatePublished - Apr 24 2014

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Keywords

  • BLM phosphorylation
  • Bloom syndrome
  • Interstrand crosslink damage
  • Non-homologous radials
  • Radial formation
  • Sister chromatid exchanges
  • Suppression

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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