Human Rap1 modulates TRF2 attraction to telomeric DNA
2015
More than two decades of genetic research have identified and
assigned main biological functions of shelterin proteins that
safeguard telomeres. However, a molecular mechanism of how each
protein subunit contributes to the protecting function of the
whole shelterin complex remains elusive. Human Repressor
activator protein 1 (Rap1) forms a multifunctional complex with
Telomeric Repeat binding Factor 2 (TRF2). Rap1-TRF2 complex is
a critical part of shelterin as it suppresses homology-directed
repair in Ku 70/80 heterodimer absence. To understand how Rap1
affects key functions of TRF2, we investigated full-length Rap1
binding to TRF2 and Rap1-TRF2 complex interactions with
double-stranded DNA by quantitative biochemical approaches. We
observed that Rap1 reduces the overall DNA duplex binding
affinity of TRF2 but increases the selectivity of TRF2 to
telomeric DNA. Additionally, we observed that Rap1 induces a
partial release of TRF2 from DNA duplex. The improved TRF2
selectivity to telomeric DNA is caused by less pronounced
electrostatic attractions between TRF2 and DNA in Rap1
presence. Thus, Rap1 prompts more accurate and selective TRF2
recognition of telomeric DNA and TRF2 localization on
single/double-strand DNA junctions. These quantitative
functional studies contribute to the understanding of the
selective recognition of telomeric DNA by the whole shelterin
complex.
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