Remodeling and destabilization of chromosome 1 pericentromeric heterochromatin by SSX proteins

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.

Evaluating the Probability of CRISPR-based Gene Drive Contaminating Another Species

“…The process of gene duplication (or even n-plication) is commonplace (Clark and Donoghue 2018b;Harari et al 2018;Moriyama and Koshiba-Takeuchi 2018) . Local amplification of sequences is also very frequent Traynor et al 2019) and this may increase the probability of accidents to a further unknown level.…”

A functional genetic screen identifies the Mediator complex as essential for SSX2-induced senescence

“…IMR90 cells were cultured in EMEM (Sigma Aldrich, Brondby, Denmark), 10% FBS and penicillin/streptomycin. IMR90 cells were transduced with a lentiviral vector for expression of doxycyclineinducible SSX2 expression as previously described 14 .…”

“…They are also ectopically expressed in many types of tumors, such as 40% of melanomas and up to 65% of breast cancers 12,13 . The SSX family comprise nine highly identical members, which are most likely redundant in their cellular functions 14 . SSX proteins belong to the cancer/testis (CT) antigen group of tumor antigens, and T-cell and antibody responses have been detected in cancer patients 15 .…”

“…The role of SSX proteins in supporting cell proliferation and their ability to induce senescence suggest that these CT antigens may have oncogenic potential. SSX proteins are DNA-binding factors that regulate chromatin structure and Polycomb function 14,15,17,18 . They contain an SSX repression (SSXRD) domain and a Kruppel-associated box (KRAB), which seem to be important for chromatin-binding and -rearrangement, respectively 14 .…”

Interaction between Polycomb and SSX Proteins in Pericentromeric Heterochromatin Function and Its Implication in Cancer

“…Instead, the KRAB domain of SSX has been demonstrated to interact with SSX2IP and RAB3IP [83], but the consequences of these potential interactions remains unexplored. We have recently reported that the SSXRD structurally resembles a C2H2 binding zinc finger domain, which is one of the most common eukaryotic DNA binding domains and is frequently found in transcription factors [74]. SSX proteins contain a short alpha-helical structure similar to the one that mediates binding to the major groove of DNA in C2H2 zinc finger motifs (C2H2-ZNF) [84].…”