SA1 binds directly to DNA via its unique AT-hook to promote sister chromatid cohesion at telomeres

Abstract

SummarySister chromatid cohesion relies on cohesin, a complex comprising a tri-partite ring and a peripheral subunit Scc3, which is found as two related isoforms SA1 and SA2 in vertebrates. There is a division of labor between the vertebrate cohesin complexes; SA1-cohesin is required at telomeres and SA2-cohesin at centromeres. Depletion of SA1 has dramatic consequences for telomere function and genome integrity, but the mechanism by which SA1-cohesin mediates cohesion at telomeres is not well understood. Here we dissect the individual contribution of SA1 and the ring subunits to telomere cohesion and show that telomeres rely heavily on SA1 and to a lesser extent on the ring for cohesion. Using chromatin immunoprecipitation we show that SA1 is highly enriched at telomeres, is decreased at mitosis when cohesion is resolved, and is increased when cohesion persists. Overexpression of SA1 alone was sufficient to induce cohesion at telomeres, independent of the cohesin ring and dependent on its unique (not found in SA2) N-terminal domain, which we show binds to telomeric DNA through an AT-hook motif. We suggest that a specialized cohesion mechanism may be required to accommodate the high level of DNA replication-associated repair at telomeres.

Loss of Tumor Suppressor STAG2 Promotes Telomere Recombination and Extends the Replicative Lifespan of Normal Human Cells

“…Homologous recombination between sister telomeres can only occur in a small window of the cell cycle: between post-replication in S phase and separation in mitosis. Resolution of telomere cohesion normally occurs in late S/G2 and is complete by prophase (14). By contrast, in STAG2-depleted cells telomeres remain cohered throughout G2 and into mitosis.…”

“…Cohesion is mediated by the cohesin ring, a tripartite structure comprised of SMC1, SMC3, and SCC1, and a peripheral SA subunit found as two isoforms SA1 and SA2, which are required for telomere and centromere cohesion, respectively (12, 13). SA1 is distinguished by a unique N-terminal 72 amino acid domain that contains a DNA-binding AT-hook motif and binds the shelterin subunit TRF1 (14), which facilitates its association with telomeric DNA (15). …”

Chromosome Dynamics during Mitosis

“…It has also been reported that targeted inactivation of SA2 in a human cell line causes cohesion defects and aneuploidy (Solomon et al 2011). In the future, it will be of importance to determine how cohesin-SA1 and -SA2 are targeted to specific loci at a mechanistic level, although there is evidence that SA1 might use its AT-hook motif for telomere binding (Bisht et al 2013). …”

Subtelomeric CTCF and cohesin binding site organization using improved subtelomere assemblies and a novel annotation pipeline

“…Cohesin subunit STAG1 is recruited to telomere repeats by the shelterin protein TINF2, and this interaction is required for telomeric sister chromatid cohesion and efficient telomere replication (Canudas and Smith 2009;Remeseiro et al 2012). STAG1 binds directly to telomere repeat DNA through a unique AT hook, and overexpression of STAG1 alone is sufficient to induce cohesion at telomeres independently of cohesin ring components (Bisht et al 2013). In contrast, colocalized cohesin ring components and CTCF both contribute to subtelomeric TERRA transcriptional regulation and telomere end protection (Deng et al 2012).…”