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Proteolysis and ubiquitination
This network was generated using Cytoscape V2.2, yFiles/circular layout with a lexically-driven XML plug-in to the Agilent Literature Search, curated and color coded in Adobe Illustrator CS2.
Following DNA double-strand breaks, BRCA1 (top violet node) is phosphorylated by upstream ATM and ATR kinases and controls downstream Chk1 kinase activity (chek2; brown node), which regulates the damage-induced intra-S-phase checkpoint and the G2/M checkpoint. BRCA1 also associates with Rad51 (grey node) and mediates homologous recombination, which is an important mechanism for DNA double-strand break repair in S and G2 phases. BRCA1 localizes to double-strand breaks (DSB) sites with gamma-H2AX.
Recently it has been shown that RNF8 (RING finger 8, blue node) is an E3 ubiquitin ligase that catalyzes regulatory ubiquitination (or ubiquitylation) at DNA lesions. RNF8 rapidly accumulates into IR-induced foci that colocalize with gamma-H2AX. Remarkably, RNF8 is critical for the relocalization of BRCA1 into these IR-induced foci. RNF8 physically interacts with the E2 conjugating enzyme UBC13, and together these proteins can catalyze histone K63-linked ubiquitination. Di-ubiquitination of H2AX, being the main product of RNF8- dependent activity, indicates that the H2A/H2AX ubiquitination in response to DNA damage might be structurally distinct from the repression by mono-ubiquitination. In summary, RNF8 fulfills the criteria for being the E3 ubiquitin ligase that collaborates with UBC13 to mediate the ubiquitin-dependent recruitment of the BRCA1 complexes to sites of damage chromatin.
Very recently a novel ubiquitin-specific protease Scrawny (SCNY; yellow node, bottom) has been identified that targets a histone protein H2B. SCNY is a member of a large family of ubiquitin-specific proteases, with 16 members in budding yeast, 18 in Drosophila, and more than 50 in mammals. It is remarkable that the removal of ubiquitin from H2B by SCNY is required to prevent premature stem cell differentiation in adult stem cells. It is becoming increasingly clear that ubiquitin signaling to chromatin is pervasive in gene regulation. For example, ubiquitination of H2A is associated with silencing of genes by Polycomb repressor proteins, and a histone acetyltransferase complex uses an H2A-deubiquitinating enzyme to activate Polycomb-repressed genes. Polycomb proteins play a major role in stem cell biology and may be misregulated in cancer stem cells as well.
Identifying proteins that associate with SCNY could provide insight into how SCNY activity is regulated, including how it is targeted to stem cell-repressed genes. Because this is a relatively new field of study, more ubiquitin-specific proteases that can deubiquitinate H2B and regulate gene expression are likely to be identified.
Recently it has been shown that RNF8 (RING finger 8, blue node) is an E3 ubiquitin ligase that catalyzes regulatory ubiquitination (or ubiquitylation) at DNA lesions. RNF8 rapidly accumulates into IR-induced foci that colocalize with gamma-H2AX. Remarkably, RNF8 is critical for the relocalization of BRCA1 into these IR-induced foci. RNF8 physically interacts with the E2 conjugating enzyme UBC13, and together these proteins can catalyze histone K63-linked ubiquitination. Di-ubiquitination of H2AX, being the main product of RNF8- dependent activity, indicates that the H2A/H2AX ubiquitination in response to DNA damage might be structurally distinct from the repression by mono-ubiquitination. In summary, RNF8 fulfills the criteria for being the E3 ubiquitin ligase that collaborates with UBC13 to mediate the ubiquitin-dependent recruitment of the BRCA1 complexes to sites of damage chromatin.
Very recently a novel ubiquitin-specific protease Scrawny (SCNY; yellow node, bottom) has been identified that targets a histone protein H2B. SCNY is a member of a large family of ubiquitin-specific proteases, with 16 members in budding yeast, 18 in Drosophila, and more than 50 in mammals. It is remarkable that the removal of ubiquitin from H2B by SCNY is required to prevent premature stem cell differentiation in adult stem cells. It is becoming increasingly clear that ubiquitin signaling to chromatin is pervasive in gene regulation. For example, ubiquitination of H2A is associated with silencing of genes by Polycomb repressor proteins, and a histone acetyltransferase complex uses an H2A-deubiquitinating enzyme to activate Polycomb-repressed genes. Polycomb proteins play a major role in stem cell biology and may be misregulated in cancer stem cells as well.
Identifying proteins that associate with SCNY could provide insight into how SCNY activity is regulated, including how it is targeted to stem cell-repressed genes. Because this is a relatively new field of study, more ubiquitin-specific proteases that can deubiquitinate H2B and regulate gene expression are likely to be identified.
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