RNF20–RNF40: A ubiquitin‐driven link between gene expression and the DNA damage response

Abstract

a b s t r a c tThe DNA damage response (DDR) is emerging as a vast signaling network that temporarily modulates numerous aspects of cellular metabolism in the face of DNA lesions, especially critical ones such as the double strand break (DSB). The DDR involves extensive dynamics of protein post-translational modifications, most notably phosphorylation and ubiquitylation. The DSB response is mobilized primarily by the ATM protein kinase, which phosphorylates a plethora of key players in its various branches. It is based on a core of proteins dedicated to the damage response, and a cadre of proteins borrowed temporarily from other cellular processes to help meet the challenge. A recently identified novel component of the DDR pathway -histone H2B monoubiquitylationexemplifies this principle. In mammalian cells, H2B monoubiquitylation is driven primarily by an E3 ubiquitin ligase composed of the two RING finger proteins RNF20 and RNF40. Generation of monoubiquitylated histone H2B (H2Bub) has been known to be coupled to gene transcription, presumably modulating chromatin decondensation at transcribed regions. New evidence indicates that the regulatory function of H2Bub on gene expression can selectively enhance or suppress the expression of distinct subsets of genes through a mechanism involving the hPAF1 complex and the TFIIS protein. This delicate regulatory process specifically affects genes that control cell growth and genome stability, and places RNF20 and RNF40 in the realm of tumor suppressor proteins. In parallel, it was found that following DSB induction, the H2B monoubiquitylation module is recruited to damage sites where it induces local H2Bub, which in turn is required for timely recruitment of DSB repair protein and, subsequently, timely DSB repair. This pathway represents a crossroads of the DDR and chromatin organization, and is a typical example of how the DDR calls to action functional modules that in unprovoked cells regulate other processes. Ó 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. The DNA damage response: borrowing functional modules in an emergencyCellular metabolism is controlled by numerous, interlocked signaling networks. These networks are constantly responding to internal and external stimuli related to the cell's normal life cycle and functions, and to threats to its well being. A major threat to cellular homeostasis is subversion of its genomic stability, which may lead to undue cell death or to neoplasia [1,2]. DNA damage caused by internal or external damaging agents is a major danger to the integrity of the cellular genome. The cellular defense system against this threat is the DNA damage response (DDR) -an elaborate signaling network activated by DNA damage, which swiftly modulates many physiological processes [3,4]. A strong trigger of the DDR is the DNA double-strand break (DSB) [5,6]. DSBs are induced by ionizing radiation, radiomimetic chemicals, reactive oxygen species formed in the course of normal metabolism, and can also result from replic...

BRUCE regulates DNA double-strand break response by promoting USP8 deubiquitination of BRIT1

“…Another well-established ubiquitination cascade is the MDC1-dependent K63 polyubiquitination of histones H2A and H2AX at damaged chromatin, creating Ubbinding sites for RAP80 and BRAC1 accumulation at DNA breaks (20)(21)(22)(23)(24)(25)(26)36). Another is the monoubiquitination of histone H2B by the heterodimeric E3 ligases RNF20 and RNF40 and their functional partner WAC; together they facilitate chromatin relaxation for DNA repair, linking gene expression with DDR (48)(49)(50)(51).…”

Recognition, signaling, and repair of DNA double-strand breaks produced by ionizing radiation in mammalian cells: The molecular choreography

“…SNFH2 is a motor ATPase. The RAD6 E2 ubiquitin-conjugating enzyme may act in concert with RNF20-RNF40 [290] in a reaction that depends on the MRN complex. The NuA4 complex can interact with monoubiquitylated H2B.…”

“…In undamaged cells, monoubiquitylated histone H2B is an important regulator of gene expression and tumor suppression (reviewed in [290]). The human RNF20-RNF40 heterodimeric E3 ubiquitin ligase mediates monoubiquitylation of histone H2B [291,292], which is an essential step for the chromatin remodeling and relaxation mediated by SNF2H.…”

Histone H2B monoubiquitination: roles to play in human malignancy

“…RNF20 functions with NBS1 (a member of the mammalian MRE11-RAD50 DSB repair complex) at sites of DSBs to facilitate repair through SNF2H-mediated chromatin reorganisation (Nakamura et al 2011). This process recruits factors required for both non-homologous end joining (XRCC4 and Ku80) and homologous recombination repair (HRR; RAD51, BRCA1 and BRCA2) , Nakamura et al 2011, Shiloh et al 2011.…”