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The BLM helicase functions in alternative lengthening of telomeres
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The BLM helicase functions in alternative lengthening of telomeres
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The BLM helicase functions in alternative lengthening of telomeres
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Dissertation
The BLM helicase functions in alternative lengthening of telomeres
2004
Overview
Somatic cells from persons with the inherited chromosome breakage syndrome Bloom syndrome (BS) feature excessive chromosome breakage, intra- and inter-chromosomal homologous exchanges and telomeric associations. The gene mutated in BS, BLM, encodes a RecQ-like ATP-dependent 3′-to-5 ′ helicase that presumably functions in some types of DNA transactions. As the absence of BLM is associated with excessive recombination, in vitro experiments have tested the ability of BLM to suppress recombination and/or resolve recombination intermediates. In vitro, BLM promotes branch migration of Holliday junctions, resolves D-loops and unwinds G-quadruplex DNA. A function for BLM in maintaining telomeres is suggested by the latter, since D-loops and perhaps G-quadruplex structures are thought to be present at telomeres. In the present study, the association of BLM with telomeres was investigated. Given the association of BLM with recombination, it was of particular interest to determine the nuclear localization of BLM with respect to telomeres in cells using recombinational pathways for telomere lengthening, termed ALT. Using the telomere repeat protein TRF2 as a telomere marker, we demonstrate that BLM co-localizes with telomeres in cells using ALT, but not in telomerase-positive or primary cells. BLM colocalizes with TRF2 in foci actively synthesizing DNA during late S and G2/M; colocalization is enriched during these phases of the cell cycle when ALT is thought to occur. By immunoprecipitation, BLM associates with telomeres and TRF2 in cells using ALT. In S. cerevisiae , we demonstrate that BLM expression rescues a defect in recombinational telomere lengthening associated with absence of SGS1. These data establish a spatial and temporal association of BLM with telomere synthesis in cells using ALT and demonstrate conserved function(s) for BLM and SGS1 in ALT. Additionally, the regulation of BLM activity using telomere substrates was investigated in vitro. We find that TRF1 and TRF2 physically and functionally interact with BLM in vitro. TRF2 stimulates BLM unwinding of telomeric and non-telomeric substrates. Conversely, TRF1 inhibits BLM unwinding of telomeric substrates only. Neither TRF1 nor TRF2 regulate unwinding activity of the UvrD helicase. Finally, BLM helicase activity is stimulated by TRF2 with equimolar concentrations of TRF1, but not when TRF1 is present in molar excess. Based on these data, we present a model for the coordinated regulation of BLM helicase activity by TRF1 and TRF2 at telomeres in cells using ALT.
