Abstract
Cohesin is an evolutionarily conserved protein complex that plays a role in many biological processes: it ensures faithful chromosome segregation, regulates gene expression and preserves genome stability. In mammalian cells, the mitotic cohesin complex consists of two structural maintenance of chromosome proteins, SMC1A and SMC3, the kleisin protein RAD21 and a fourth subunit either STAG1 or STAG2. Meiotic paralogs in mammals were reported for SMC1A, RAD21 and STAG1/STAG2 and are called SMC1B, REC8 and STAG3 respectively. It is believed that SMC1B is only a meiotic-specific cohesin member, required for sister chromatid pairing and for preventing telomere shortening. Here we show that SMC1B is also expressed in somatic mammalian cells and is a member of a mitotic cohesin complex. In addition, SMC1B safeguards genome stability following irradiation whereas its ablation has no effect on chromosome segregation. Finally, unexpectedly SMC1B depletion impairs gene transcription, particularly at genes mapping to clusters such as HOX and PCDHB. Genome-wide analyses show that cluster genes changing in expression are enriched for cohesin-SMC1B binding.
Highlights
Determines meiotic chromatin loop/axes organization, contributes to sister chromatid cohesion and chromosome synapsis, and protects telomeres from rearrangement[28,29,30]
We found that Smc1b is highly expressed in the testes when analyzed by quantitative reverse-transcription PCR (RT-qPCR), but surprisingly it is expressed in brain, heart and spleen (Fig. 1A)
Published works did not report the expression of Smc1b in primary somatic cells[31], though its expression has been shown in embryonic stem cells[32]
Summary
Determines meiotic chromatin loop/axes organization, contributes to sister chromatid cohesion and chromosome synapsis, and protects telomeres from rearrangement[28,29,30]. There is no obvious somatic phenotype of Smc1b−/− mice. We present evidence that SMC1B is expressed in both somatic mouse tissues and human primary fibroblasts and associates with SMC3 and RAD21, making it a member of the mitotic cohesin complex. We find that SMC1B participates in cellular response to DNA damage, whereas SMC1B silencing does not affect both chromosome number and morphology. We revealed that SMC1B depletion leads to gene expression dysregulation; in particular, significant changes occurred in genes mapping to clusters. ChIP-seq data show that dysregulated cluster genes are enriched for cohesin-SMC1B. Starting out by addressing the question of whether SMC1B is expressed in mammalian cells, we showed that SMC1B participates in maintaining genome stability, and revealed a new role for cohesin-SMC1B in gene expression
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