Abstract
Cohesin is a multi-protein complex that tethers sister chromatids during mitosis and mediates DNA repair, genome compartmentalisation and regulation of gene expression. Cohesin subunits frequently acquire cancer loss-of-function alterations and act as tumour suppressors in several tumour types. This has led to increased interest in cohesin as potential target in anti-cancer therapy. Here we show that the loss-of-function of STAG2, a core component of cohesin and an emerging tumour suppressor, leads to synthetic dependency of mutated cancer cells on its paralog STAG1. STAG1 and STAG2 share high sequence identity, encode mutually exclusive cohesin subunits and retain partially overlapping functions. We inhibited STAG1 and STAG2 in several cancer cell lines where the two genes have variable mutation and copy number status. In all cases, we observed that the simultaneous blocking of STAG1 and STAG2 significantly reduces cell proliferation. We further confirmed the synthetic lethal interaction developing a vector-free CRISPR system to induce STAG1/STAG2 double gene knockout. We provide strong evidence that STAG1 is a promising therapeutic target in cancers with inactivating alterations of STAG2.
Highlights
Cohesin is an evolutionarily conserved complex composed of four core proteins (SMC1A, SMC3, RAD21 and either STAG2 or STAG1) that form a ring-shaped structure able to encircle chromatin [1]
We found that viable cells after the simultaneous silencing of STAG1 and STAG2 were significantly lower than the control (Figure 2B), supporting synthetic lethality between the two genes
Synthetic lethality between cohesin and PARP has been explained by their respective roles in recovering and maintaining the integrity of stalled replication forks [26]
Summary
Cohesin is an evolutionarily conserved complex composed of four core proteins (SMC1A, SMC3, RAD21 and either STAG2 or STAG1) that form a ring-shaped structure able to encircle chromatin [1]. Cohesin is responsible for the cohesion of sister chromatids and proper chromosome segregation during mitosis [1, 2]. Besides this canonical role, cohesin is involved in a plethora of other functions including DNA replication and repair, regulation of gene expression and genome compartmentalisation [3, 4]. Several cancers with inactivating alterations in the cohesin complex maintain a nearly normal karyotype This led to speculation that the alteration of other cohesin functions, such as transcriptional deregulation or defective DNA repair, may contribute to cancer [7, 8]
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