An Arginine-rich Motif of Ring Finger Protein 4 (RNF4) Oversees the Recruitment and Degradation of the Phosphorylated and SUMOylated Krüppel-associated Box Domain-associated Protein 1 (KAP1)/TRIM28 Protein during Genotoxic Stress

Kuo, Ching‐Ying; Li, Xu; Kong, Xiang Qian; Luo, Cheng; Chang, Che-Chang; Chung, Yiyin; Shih, Hsiu Ming; Li, Keqin Kathy; Ann, David K.

doi:10.1074/jbc.m114.555672

Cited by 42 publications

(50 citation statements)

References 58 publications

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“…STUbL E3 ligases, such as RNF4, promote the polyubiquitination and degradation of polySUMOylated proteins (35,36). RNF4 is a strong regulator of DNA damage response (19)(20)(21)(22)(41)(42)(43), suggesting that it polyubiquitinates DNA repair proteins, which are themselves polySUMOylated. We therefore hypothesized that RNF4, which contains a tandem repeat of SIMs (44), might be the STUbL that promotes the degradation of polySUMOylated FANCA ( Figure 5).…”

Section: I939smentioning

confidence: 99%

RNF4-mediated polyubiquitination regulates the Fanconi anemia/BRCA pathway

Xie¹,

Kim²,

Moreau³

et al. 2015

J. Clin. Invest.

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Section: I939smentioning

confidence: 99%

RNF4-mediated polyubiquitination regulates the Fanconi anemia/BRCA pathway

Xie¹,

Kim²,

Moreau³

et al. 2015

J. Clin. Invest.

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“…The presently identified enzymes that act on central components of the DDR are displayed. Aside from PTM reversal, activated checkpoint components can also be removed either by proteasomal degradation, as is the case for p53 and phosphorylated KAP1 (Kuo et al, 2014) (indicated by the red cross), or by exchange, as occurs with cH2AX in a process mediated by the histone chaperone FACT. Chromatin compaction is another important impediment of the DDR.…”

Section: Removal Of Modified Proteinsmentioning

confidence: 99%

The same, only different – DNA damage checkpoints and their reversal throughout the cell cycle

Shaltiël

Krenning

Bruinsma

et al. 2015

Journal of Cell Science

252

272

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Cell cycle checkpoints activated by DNA double-strand breaks (DSBs) are essential for the maintenance of the genomic integrity of proliferating cells. Following DNA damage, cells must detect the break and either transiently block cell cycle progression, to allow time for repair, or exit the cell cycle. Reversal of a DNA-damageinduced checkpoint not only requires the repair of these lesions, but a cell must also prevent permanent exit from the cell cycle and actively terminate checkpoint signalling to allow cell cycle progression to resume. It is becoming increasingly clear that despite the shared mechanisms of DNA damage detection throughout the cell cycle, the checkpoint and its reversal are precisely tuned to each cell cycle phase. Furthermore, recent findings challenge the dogmatic view that complete repair is a precondition for cell cycle resumption. In this Commentary, we highlight cell-cycle-dependent differences in checkpoint signalling and recovery after a DNA DSB, and summarise the molecular mechanisms that underlie the reversal of DNA damage checkpoints, before discussing when and how cell fate decisions after a DSB are made.

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“…Phosphorylation of TRIM28 is also required for its function in transcription repression (55). The active TRIM28, once phosphorylated and SUMOylated, has a shorter half-life and is targeted for degradation by RNF4 (56). This pattern of behaviors suggests that after silencing a specific chromatin region, TRIM28 function for that region is subsequently turned off.…”

Section: Rapid Degradation Of Full-length Zfp809 Protein In Differentmentioning

confidence: 99%

Differential control of retrovirus silencing in embryonic cells by proteasomal regulation of the ZFP809 retroviral repressor

Wang

Goff

2017

Proc. Natl. Acad. Sci. U.S.A.

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Replication of the murine leukemia viruses is strongly suppressed in mouse embryonic stem (ES) cells. Proviral DNAs are formed normally but are then silenced by a large complex bound to DNA by the ES cell-specific zinc-finger protein ZFP809. We show here that ZFP809 expression is not regulated by transcription but rather by protein turnover: ZFP809 protein is stable in embryonic cells but highly unstable in differentiated cells. The protein is heavily modified by the accumulation of polyubiquitin chains in differentiated cells and stabilized by the proteasome inhibitor MG132. A short sequence of amino acids at the C terminus of ZFP809, including a single lysine residue (K391), is required for the rapid turnover of the protein. The silencing cofactor TRIM28 was found to promote the degradation of ZFP809 in differentiated cells. These findings suggest that the stem cell state is established not only by an unusual transcriptional profile but also by unusual regulation of protein levels through the proteasomal degradation pathway. Infection of these cells by MLVs results in normal virus entry, reverse transcription of the viral RNA, and integration of viral DNA, but the proviral DNA is then transcriptionally silenced. A specific DNA sequence used to prime viral DNA synthesis, the primer binding site complementary to the 3′ portion of proline tRNA (PBSpro), is present on those viruses that are most strongly and rapidly silenced (7-10). A large protein complex, specifically expressed in ES cells, binds to the PBSpro sequence to mediate the transcriptional repression of proviral DNA (5,9,11,12). This silencing complex contains the transcriptional repressor TRIM28, also known as KAP1 or TIF1β (6), and is tethered to the PBSpro DNA by ZFP809, a zinc-finger protein with sequence-specific DNA-binding activity (13). TRIM28 acts as a scaffold for a number of factors that mediate the silencing of the nearby DNA, including the NuRD histone deacetylase complex, histone H3K9 methyltransferase ESET, and heterochromatin protein 1 (14-17). TRIM28, a RING-domain protein, also plays an important role in the protein modification pathway. Like other members of the RING domain family, TRIM28 is an E3 ligase that mediates transfer of ubiquitin or the small ubiquitin-like modifier (SUMO) to target substrates (18,19). ZFP809 contains two domains, a KRAB box at the N terminus that is responsible for the interaction with TRIM28 and a zincfinger domain containing seven zinc fingers that provide its sequence-specific DNA-binding activity (Fig. 1A). Whereas most of the components of the silencing complex are expressed ubiquitously, ZFP809 is expressed specifically in embryonic cells and not in differentiated cells (13,20). ZFP809 is the key ES cellspecific component of the silencing complex. Ectopic expression of suitable forms of ZFP809 in differentiated cells is sufficient to induce the formation of the DNA-binding silencing complex and to establish the silencing in those cells (13), suggesting that the lack of restriction of MLVs in differen...

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An Arginine-rich Motif of Ring Finger Protein 4 (RNF4) Oversees the Recruitment and Degradation of the Phosphorylated and SUMOylated Krüppel-associated Box Domain-associated Protein 1 (KAP1)/TRIM28 Protein during Genotoxic Stress

Cited by 42 publications

References 58 publications

RNF4-mediated polyubiquitination regulates the Fanconi anemia/BRCA pathway

RNF4-mediated polyubiquitination regulates the Fanconi anemia/BRCA pathway

The same, only different – DNA damage checkpoints and their reversal throughout the cell cycle

Differential control of retrovirus silencing in embryonic cells by proteasomal regulation of the ZFP809 retroviral repressor

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