Structure and functional mapping of the KRAB‐KAP1 repressor complex

Stoll, Guido A.; Pandiloski, Ninoslav; Douse, Christopher H.; Modis, Yorgo

doi:10.15252/embj.2022111179

Cited by 13 publications

(19 citation statements)

References 62 publications

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“…2 A). Similar hydrophobic interactions also exist in other reported TRIM coiled-coiled dimeric structures, such as TRIM5 [38] , [39] , TRIM20 [40] , TRIM25 [41] , [42] , TRIM28 [43] , [44] , [45] , and TRIM69 [46] . Therefore, hydrophobic interactions are a common feature of TRIM proteins, which bind two chains together to form an antiparallel dimer.…”

Section: Discussionsupporting

confidence: 87%

TRIM56 coiled-coil domain structure provides insights into its E3 ligase functions

Lou¹,

Ma²,

Zhuang³

et al. 2023

Computational and Structural Biotechnology Journal

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Section: Discussionsupporting

confidence: 87%

TRIM56 coiled-coil domain structure provides insights into its E3 ligase functions

Lou¹,

Ma²,

Zhuang³

et al. 2023

Computational and Structural Biotechnology Journal

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“…In particular, mutations of cysteine or histidine residues in critical zinc coordinating clusters of the RING, B2, and PHD domains appear to affect protein folding and stability. Other variants that lie in the same domains as our mutations were previously shown to impair protein function [26–28,30]. It would therefore seem likely that the nontruncating mutations we found alter protein stability as well as function.…”

Section: Discussionmentioning

confidence: 54%

“…We now identified 11 missense mutations and two in-frame deletions. We placed these variants onto the known 3D structure of TRIM28, which suggested a common mechanisms for disruption of TRIM28 function, as all mutations were located in critical regions of the protein [26][27][28].…”

Section: Missense Mutations Destabilize Trim28mentioning

confidence: 99%

“…Similarly, B-box 2 is a RING-like motif (CHC4H2-type) with dual cross-braced Zn 2+ coordination, extending from cysteine 209 to histidine 240 [28]. The C209Y, C224Y, and H240N mutations may thus likewise impair B-box 2 folding and destabilize the mutant protein [26,27]. The more distal deletion R629_C631delRVC in WT132 affects the PHD domain, where cysteine 631 is part of a zinc binding cluster that is essential for autosumoylation and target gene repression before [30].…”

Section: Missense Mutations Destabilize Trim28mentioning

confidence: 99%

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TRIM28 inactivation in epithelial nephroblastoma is frequent and often associated with predisposing TRIM28 germline variants

Wegert,

Fischer,

Palhazi

et al. 2023

The Journal of Pathology

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Wilms tumors (WTs) are histologically diverse childhood cancers with variable contributions of blastema, stroma, and epithelia. A variety of cancer genes operate in WTs, including the tripartite‐motif‐containing‐28 gene (TRIM28). Case reports and small case series suggest that TRIM28 mutations are associated with epithelial morphology and WT predisposition. Here, we systematically investigated the prevalence of TRIM28 inactivation and predisposing mutations in a cohort of 126 WTs with >2/3 epithelial cells, spanning 20 years of biobanking in the German SIOP93‐01/GPOH and SIOP2001/GPOH studies. Overall, 44.4% (56/126) cases exhibited loss of TRIM28 by immunohistochemical staining. Of these, 48 could be further analyzed molecularly, revealing TRIM28 sequence variants in each case – either homozygous (~2/3) or heterozygous with epigenetic silencing of the second allele (~1/3). The majority (80%) of the mutations resulted in premature stops and frameshifts. In addition, we detected missense mutations and small deletions predicted to destabilize the protein through interference with folding of key structural elements such as the zinc‐binding clusters of the RING, B‐box‐2, and PHD domains or the central coiled‐coil region. TRIM28‐mutant tumors otherwise lacked WT‐typical IGF2 alterations or driver events, except for rare TP53 progression events that occurred with expected frequency. Expression profiling identified TRIM28‐mutant tumors as a homogeneous subset of epithelial WTs that mostly present with stage I disease. There was a high prevalence of perilobar nephrogenic rests, putative precursor lesions, that carried the same biallelic TRIM28 alterations in 7/7 cases tested. Importantly, 46% of the TRIM28 mutations were present in blood cells or normal kidney tissue, suggesting germline events or somatic mosaicism, partly supported by family history. Given the high prevalence of predisposing variants in TRIM28‐driven WT, we suggest that immunohistochemical testing of TRIM28 be integrated into diagnostic practice as the management of WT in predisposed children differs from that with sporadic tumors. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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“…KRAB-ZNFs bind to TEs and recruit KAP1 through KRAB domain[10, 12]. KAP1 in turn recruits the repressive chromatin modifier enzymes including heterochromatin protein HP1, histone H3K9 methyltransferase SETDB1, and the nucleosome remodeling and deacetylase (NuRD) complex[10, 13]. The role of KAP1 in repression of TEs is well characterized[9, 12].…”

Section: Introductionmentioning

confidence: 99%

Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymes

Patel,

Tiusanen,

Pihlajamaa

et al. 2024

Preprint

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The combination of immunotherapy and epigenetic therapy is emerging as a promising approach for cancer therapy. Epigenetic therapy can induce derepression of transposable elements (TEs) that play a major role in activation of immune response against cancer cells. However, the molecular mechanism of TE regulation by distinct chromatin modifier enzymes (CME) and in the context of p53 is still elusive. Here, we used epigenetic drugs to inhibit distinct CMEs in p53 wild-type and p53-mutant colorectal and esophageal cancer cells. We show that distinct TEs subfamilies are derepressed by inhibition of different CMEs in a cell-type specific manner with loss of p53 resulting in stronger TE derepression. We show that KAP1, a known repressor of TEs, associates with stronger derepression of specific TE subfamilies such as LTR12C, indicating that KAP1 also has an activating role in TE regulation in cancer cells upon co-inhibition of DNMT and HDAC. Co-inhibition of DNMT and HDAC activates immune response by inducing inverted repeat Alu expression, reducing ADAR1-mediated Alu RNA editing, and inducing cell type-specific TE-chimeric transcript expression. Collectively, our study demonstrates that inhibition of different CMEs results in derepression of distinct TEs in cell type-specific manner and by utilizing distinct mechanistic pathways, providing insights for epigenetic therapies that could selectively enhance anti-tumor immunity in distinct cancer types.

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Structure and functional mapping of the KRAB‐KAP1 repressor complex

Cited by 13 publications

References 62 publications

TRIM56 coiled-coil domain structure provides insights into its E3 ligase functions

TRIM56 coiled-coil domain structure provides insights into its E3 ligase functions

TRIM28 inactivation in epithelial nephroblastoma is frequent and often associated with predisposing TRIM28 germline variants

Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymes

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