Abstract
The deubiquitination of histone H2A on lysine 119 by 2A-DUB/MYSM1, BAP1, USP16, and other enzymes is required for key cellular processes, including transcriptional activation, apoptosis, and cell cycle control, during normal hematopoiesis and tissue development, and in tumor cells. Based on our finding that MYSM1 colocalizes with γH2AX foci in human peripheral blood mononuclear cells, leukemia cells, and melanoma cells upon induction of DNA double-strand breaks with topoisomerase inhibitor etoposide, we applied a mass spectrometry-based proteomics approach to identify novel 2A-DUB/MYSM1 interaction partners in DNA-damage responses. Differential display of MYSM1 binding proteins significantly enriched after exposure of 293T cells to etoposide revealed an interacting network of proteins involved in DNA damage and replication, including factors associated with poor melanoma outcome. In the context of increased DNA-damage in a variety of cell types in Mysm1-deficient mice, in bone marrow cells upon aging and in UV-exposed Mysm1-deficient skin, our current mass spectrometry data provide additional evidence for an interaction between MYSM1 and key DNA replication and repair factors, and indicate a potential function of 2A-DUB/MYSM1 in DNA repair processes.
Highlights
According to the “access–repair–restore model”, DNA damage responses (DDR) are highly orchestrated cellular processes that depend on chromatin remodeling and histone modifications, notably histone ubiquitination [1,2,3,4,5]
MYSM1 Is Recruited to γH2AX Foci upon Chemical Induction of DNA Damage with Etoposide in Human Peripheral Blood Mononuclear Cells (PBMC) and Tumor Cell Lines
Based on detected increases in a marker of DNA-damage, phosphorylated histone 2AX, in different tissues of Mysm1-deficient mice and in UV-exposed Mysm1−/− skin [33,38], we hypothesized that 2A-DUB/Mysm1 may have a direct role in DNA damage repair
Summary
According to the “access–repair–restore model”, DNA damage responses (DDR) are highly orchestrated cellular processes that depend on chromatin remodeling and histone modifications, notably histone ubiquitination [1,2,3,4,5]. After initial DSB detection and phosphorylation events mediated by checkpoint kinase ATM, E3 ubiquitin ligases, such as RNF8 and RNF168, catalyze H2A/X ubiquitination on K63 and K13-15, respectively, generating a platform for the sequential assembly and concentration of additional DNA repair proteins, like BRCA1 and 53BP1 [3,14,15,16]. Two main pathways may alternatively be utilized for actual DSB repair, depending on the cellular context: (1) template-mediated, high-fidelity homologous recombination (HR) or (2) error-prone, nonhomologous end-joining (NHEJ) [17,18]. Apart from protein interactions, chromatin environment, cell cycle phase, and DNA end resection repair, pathway choice may be regulated by the differential ubiquitination of H2A K13/15 and K127/129 via RNF168 and BRCA1 [17]. H2A K119 mono-ubiquitination has been implicated in nucleotide excision repair (NER) of bulky lesions in response to UV-damage in the skin, with particular relevance for skin cancer [22,23]
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