A role for Separase in telomere protection

Abstract

Drosophila telomeres are elongated by transposition of specialized retroelements rather than telomerase activity and are assembled independently of the sequence. Fly telomeres are protected by the terminin complex that localizes and functions exclusively at telomeres and by non-terminin proteins that do not serve telomere-specific functions. We show that mutations in the Drosophila Separase encoding gene Sse lead not only to endoreduplication but also telomeric fusions (TFs), suggesting a role for Sse in telomere capping. We demonstrate that Separase binds terminin proteins and HP1, and that it is enriched at telomeres. Furthermore, we show that loss of Sse strongly reduces HP1 levels, and that HP1 overexpression in Sse mutants suppresses TFs, suggesting that TFs are caused by a HP1 diminution. Finally, we find that siRNA-induced depletion of ESPL1, the Sse human orthologue, causes telomere dysfunction and HP1 level reduction in primary fibroblasts, highlighting a conserved role of Separase in telomere protection.

Separase prevents genomic instability by controlling replication fork speed

“…To date securine and cohesin-RAD21 are the only well-established interactors for Separase. However, the observations that Separase is involved in centriole disengagement and telomere stability ( 39 , 48 ) suggest that it might play novel roles, possibly through interaction with additional proteins. We therefore sought to identify molecular partners of Separase using immunoprecipitation followed by mass spectrometry (MS) analyses.…”

“…Separase knockout results in embryonic lethality ( 30 , 31 ) whereas its depletion by small interfering RNA (siRNA) causes chromosome missegregation and genomic instability in fission yeast, mouse and human cells ( 30 , 32 – 36 ). Moreover, Separase dysregulation has been shown to cause mitotic spindle defects, premature sister chromatid separation and lagging chromosomes ( 37 – 39 ). Here, we describe a novel role for Separase, which appears to be engaged in the regulation of replication fork speed and in maintaining genome integrity.…”

Silence at the End: How Drosophila Regulates Expression and Transposition of Telomeric Retroelements

“…In contrast, several other non-terminin proteins important for telomere function are evolutionarily conserved and their roles are not restricted to telomeres. This class of proteins includes Heterochromatin Protein 1a (HP1a) [29], Without children (Woc) [30], the MRN complex [31,32], ATM [33], Eff/UbcD1 [34], Peo/AKTIP [35] and Separase [36].…”

Cornelia de Lange syndrome: from molecular diagnosis to therapeutic approach

“…The disruption of TADs and the removal of cohesin or CTCF binding sites result in abnormal DNA domain topology, thus leading to gene expression dysregulation 14 23–25. Cohesin is also essential for genome integrity as it controls fork replication speed,26 27 promotes DNA repair by homologous recombination,28–32 safeguards telomere stability33 34 and recruits proteins involved in G2/M checkpoints 35 36. DNA damage response and gene transcription are intimately associated via cohesin.…”