The DNA repair function of the breast cancer susceptibility protein BRCA1 depends in part on its interaction with RAP80, which targets BRCA1 to DNA double-strand breaks (DSBs) through recognition of K63-linked polyubiquitin chains. The localization of BRCA1 to DSBs also requires sumoylation. We demonstrated that, in addition to having ubiquitin-interacting motifs, RAP80 also contains a SUMO-interacting motif (SIM) that is critical for recruitment to DSBs. In combination with the ubiquitin-binding activity of RAP80, this SIM enabled RAP80 to bind with nanomolar affinity to hybrid chains consisting of ubiquitin conjugated to SUMO. Furthermore, RNF4, a SUMO-targeted ubiquitin E3 ligase that synthesizes hybrid SUMO-ubiquitin chains, localized to DSBs and was critical for the recruitment of RAP80 and BRCA1 to sites of DNA damage. Our findings, therefore, connect ubiquitin- and SUMO-dependent DSB recognition, revealing that RNF4-synthesized hybrid SUMO-ubiquitin chains are recognized by RAP80 to promote BRCA1 recruitment and DNA repair.
"More recent work has revealed crucial roles for other types of ubiquitylation including monoubiquitylation and other types of polyubiquitin chain, in particular the K63 and K11 linkages (Ikeda & Dikic, 2008). Hybrid polyubiquitin chains made up of diverse ubiquitin linkages have also been detected in cells (Guzzo et al, 2012; Emmerich et al, 2013). The diverse polyubiquitin chains regulate cell functions such as gene transcription, DNA repair and replication, immune cell signalling, intracellular trafficking and many more (Hershko & Ciechanover, 1998; Kulathu & Komander, 2012). "
"In the case of arsenic trioxide, SUMO chains form on PML protein present in nuclear bodies, and RNF4 is rapidly recruited to these sites in a SIM-dependent, but RING-independent , fashion (Geoffroy et al., 2010). Similarly, DNA damage results in the accumulation of SUMO-2/3 chains at sites of DNA damage, again resulting in the recruitment of RNF4 to these localized nuclear subdomains (Galanty et al., 2012; Guzzo et al., 2012; Vyas et al., 2013; Yin et al., 2012). In contrast, heat stress or proteasome inhibition results in a global increase of SUMO chains (Golebiowski et al., 2009; Tatham et al., 2011). "
[Show abstract][Hide abstract] ABSTRACT: Dimeric RING E3 ligases interact with protein substrates and conformationally restrain the ubiquitin-E2-conjugating enzyme thioester complex such that it is primed for catalysis. RNF4 is an E3 ligase containing an N-terminal domain that binds its polySUMO substrates and a C-terminal RING domain responsible for dimerization. To investigate how RNF4 activity is controlled, we increased polySUMO substrate concentration by ablating expression of SUMO protease SENP6. Accumulation of SUMO chains in vivo leads to ubiquitin-mediated proteolysis of RNF4. In vitro we demonstrate that at concentrations equivalent to those found in vivo RNF4 is predominantly monomeric and inactive as an ubiquitin E3 ligase. However, in the presence of SUMO chains, RNF4 is activated by dimerization, leading to both substrate ubiquitylation and autoubiquitylation, responsible for degradation of RNF4. Thus the ubiquitin E3 ligase activity of RNF4 is directly linked to the availability of its polySUMO substrates.
"Many different E3 ubiquitin ligases participate in the DDR. For example, RNF2 catalyzes the monoubiquitination of H2AX contributing to ATM recruitment [32, 33], while depletion of RNF4 impairs RAP80, BRCA1, and RAD51 recruitment to sites of DNA damage [34–36]. "
[Show abstract][Hide abstract] ABSTRACT: It is widely accepted that tumorigenesis is a multistep process characterized by the sequential accumulation of genetic alterations. However, the molecular basis of genomic instability in cancer is still partially understood. The observation that hereditary cancers are often characterized by mutations in DNA repair and checkpoint genes suggests that accumulation of DNA damage is a major contributor to the oncogenic transformation. It is therefore of great interest to identify all the cellular pathways that contribute to the response to DNA damage. Recently, RNA processing has emerged as a novel pathway that may contribute to the maintenance of genome stability. In this review, we illustrate several different mechanisms through which pre-mRNA splicing and genomic stability can influence each other. We specifically focus on the role of splicing factors in the DNA damage response and describe how, in turn, activation of the DDR can influence the activity of splicing factors.
International Journal of Cell Biology 09/2013; 2013(9):153634. DOI:10.1155/2013/153634
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