Abstract
Rearrangement of the 1q12 pericentromeric heterochromatin and subsequent amplification of the 1q arm is commonly associated with cancer development and progression and may result from epigenetic deregulation. In many premalignant and malignant cells, loss of 1q12 satellite DNA methylation causes the deposition of polycomb factors and formation of large polycomb aggregates referred to as polycomb bodies. Here, we show that SSX proteins can destabilize 1q12 pericentromeric heterochromatin in melanoma cells when it is present in the context of polycomb bodies. We found that SSX proteins deplete polycomb bodies and promote the unfolding and derepression of 1q12 heterochromatin during replication. This further leads to segregation abnormalities during anaphase and generation of micronuclei. The structural rearrangement of 1q12 pericentromeric heterochromatin triggered by SSX2 is associated with loss of polycomb factors, but is not mediated by diminished polycomb repression. Instead, our studies suggest a direct effect of SSX proteins facilitated though a DNA/chromatin binding, zinc finger-like domain and a KRAB-like domain that may recruit chromatin modifiers or activate satellite transcription. Our results demonstrate a novel mechanism for generation of 1q12-associated genomic instability in cancer cells.
Highlights
Genome instability is a hallmark of cancer and plays a key role in tumor initiation and progression [1]
Because we and others recently found that PcG bodies form when PRC1 proteins accumulate on the 1q12 pericentromeric heterochromatin (PCH) in response to demethylation of this domain in premalignant and malignant cells [26,35], we speculated that SSX2-mediated depletion of PcG bodies might perturb the epigenetic control of the 1q12 domain
We demonstrated that satellite II transcripts are associated with PcG bodies (Supplementary Figure S14H), the above results suggest that the genomic instability induced by SSX2 is independent of 1q12 satellite II and III transcription, and further supports a direct effect of SSX proteins on the structure and stabilization of 1q12 PCH
Summary
Genome instability is a hallmark of cancer and plays a key role in tumor initiation and progression [1]. The chromosome 1q12 region contains the largest heterochromatin site in the genome, comprising a megabase stretch of satellite II and III DNA repeats. This pericentromeric heterochromatin (PCH) structure is prone to breakage and the resulting translocations and duplications of the 1q arm are among the most frequent genetic aberrations in cancer [2]. 1q duplications may contribute to tumor development by increasing the dosage of cancer driver genes [11]. This is exemplified in breast cancer, where a region of the 1q arm that encodes genes that support a cancer stem cell phenotype is amplified in 10–30% of primary tumors and 70% of recurring tumors [12]
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