CTDP1 regulates breast cancer survival and DNA repair through BRCT-specific interactions with FANCI

Hu, Wen Feng; Krieger, Kimiko L.; Lagundžin, Dragana; Li, Xueli; Cheung, Ronald S.; Taniguchi, Toshiyasu; Johnson, Keith R.; Bessho, Tadayoshi; Monteiro, Alvaro N.A.; Woods, Nicholas T.

doi:10.1038/s41420-019-0185-3

Cited by 15 publications

(15 citation statements)

References 62 publications

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“…and whether it alters FANCD2 ubiquitination in cells. CTDP1 and PTEN are phosphatases known to act in the FA pathway, although neither have been demonstrated to act directly on FANCI (Vuono et al, 2016;Hu et al, 2019). Our in vitro reconstitution system will be useful for answering mechanistic questions regarding FANCI dephosphorylation and for identifying potential phosphatases that regulate the FA pathway.…”

Section: Discussionmentioning

confidence: 99%

ATR-Mediated FANCI Phosphorylation Regulates Both Ubiquitination and Deubiquitination of FANCD2

Tan

Twest

Murphy

et al. 2020

Front. Cell Dev. Biol.

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DNA interstrand crosslinks (ICLs) are a physical barrier to replication and therefore toxic to cell viability. An important mechanism for the removal of ICLs is the Fanconi Anemia DNA repair pathway, which is initiated by mono-ubiquitination of FANCD2 and its partner protein FANCI. Here, we show that maintenance of FANCD2 and FANCI proteins in a monoubiquitinated form is regulated by the ATR-kinase. Using recombinant proteins in biochemical reconstitution experiments we show that ATR directly phosphorylates FANCI on serine 556, 559, and 565 to stabilize its association with DNA and FANCD2. This increased association with DNA stimulates the conjugation of ubiquitin to both FANCI and FANCD2, but also inhibits ubiquitin deconjugation. Using phosphomimetic and phosphodead mutants of FANCI we show that S559 and S565 are particularly important for protecting the complex from the activity of the deubiquitinating enzyme USP1:UAF1. Our results reveal a major mechanism by which ATR kinase maintains the activation of the FA pathway, by promoting the accumulation of FANCD2 in the ubiquitinated form active in DNA repair.

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Section: Discussionmentioning

confidence: 99%

ATR-Mediated FANCI Phosphorylation Regulates Both Ubiquitination and Deubiquitination of FANCD2

Tan

Twest

Murphy

et al. 2020

Front. Cell Dev. Biol.

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“…Two unique shRNA constructs targeting SHMT1 (TRCN000034766 and TRCN000034767; shSHMT1 #1 and #2) and a nontargeting scrambled control (shScr) in pLKO.1 were used in this study (Sigma). The lentiviral supernatant was produced by calcium phosphate transfection into 293FT cells, as described previously (17), and used to transduce MIA PaCa-2 and PANC 10.05 cells. The transduced cells were selected with puromycin for 5 days before use in cytotoxicity assays.…”

Section: Gemcitabine Cytotoxicity Assaymentioning

confidence: 99%

The Proteomic Landscape of Pancreatic Ductal Adenocarcinoma Liver Metastases Identifies Molecular Subtypes and Associations with Clinical Response

Law

Lagundžin

Clement

et al. 2020

Clinical Cancer Research

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Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease that can be separated into distinct subtypes based on molecular signatures. Identifying PDAC subtype-specific therapeutic vulnerabilities is necessary to develop precision medicine approaches to treat PDAC. Experimental Design: A total of 56 PDAC liver metastases were obtained from the UNMC Rapid Autopsy Program and analyzed with quantitative proteomics. PDAC subtypes were identified by principal component analysis based on protein expression profiling. Proteomic subtypes were further characterized by the associated clinical information, including but not limited to survival analysis, drug treatment response, and smoking and drinking status. Results: Over 3,960 proteins were identified and used to delineate four distinct PDAC microenvironment subtypes: (i) metabolic; (ii) progenitor-like; (iii) proliferative; and (iv) inflammatory. PDAC risk factors of alcohol and tobacco consumption correlate with subtype classifications. Enhanced survival is observed in FOLFIRINOX treated metabolic and progenitor-like subtypes compared with the proliferative and inflammatory subtypes. In addition, TYMP, PDCD6IP, ERAP1, and STMN showed significant association with patient survival in a subtype-specific manner. Gemcitabine-induced alterations in the proteome identify proteins, such as serine hydroxymethyltransferase 1, associated with drug resistance. Conclusions: These data demonstrate that proteomic analysis of clinical PDAC liver metastases can identify molecular signatures unique to disease subtypes and point to opportunities for therapeutic development to improve the treatment of PDAC.

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“…The major protein pulled down with JMJD6-Ex5 was FCP1 (TFIIF-associating CTD phosphatase). FCP1 dephosphorylates Ser2 and Ser5 of the C-terminal domain of RNA polymerase II and is thus involved in mRNA-transcription and in the DNA damage response [ 31 , 32 , 33 ]. We confirmed the interaction of FCP1 with JMJD6-Ex5 in an independent immunoprecipitation experiment.…”

Section: Discussionmentioning

confidence: 99%

JMJD6 Regulates Splicing of Its Own Gene Resulting in Alternatively Spliced Isoforms with Different Nuclear Targets

Raguz

Heim

Engal

et al. 2020

IJMS

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Jumonji-domain-containing protein 6 (JMJD6) is a Fe(II) and 2-oxogluterate (2OG) dependent oxygenase involved in gene regulation through post-translationally modifying nuclear proteins. It is highly expressed in many cancer types and linked to tumor progression and metastasis. Four alternatively-spliced jmjd6 transcripts were annotated. Here, we focus on the two most abundantly expressed ones, which we call jmjd6-2 and jmjd6-Ex5. TCGA SpliceSeq data revealed a significant decrease of jmjd6-Ex5 transcripts in patients and postmortem tissue of several tumors. The two protein isoforms are distinguished by their C-terminal sequences, which include a serine-rich region (polyS-domain) in JMJD6-2 that is not present in JMJD6-Ex5. Immunoprecipitation followed by LC-MS/MS for JMJD6-Ex5 shows that different sets of proteins interact with JMJD6-2 and JMJD6-Ex5 with only a few overlaps. In particular, we found TFIIF-associating CTD phosphatase (FCP1), proteins of the survival of motor neurons (SMN) complex, heterogeneous nuclear ribonucleoproteins (hnRNPs) and upstream binding factor (UBF) to interact with JMJD6-Ex5. Like JMJD6-2, both UBF and FCP1 comprise a polyS-domain. The polyS domain of JMJD6-2 might block the interaction with polyS-domains of other proteins. In contrast, JMJD6-2 interacts with many SR-like proteins with arginine/serine-rich (RS)-domains, including several splicing factors. In an HIV-based splicing reporter assay, co-expression of JMJD6-2 inhibited exon inclusion, whereas JMJD6-Ex5 did not have any effect. Furthermore, the silencing of jmjd6 by siRNAs favored jmjd6-Ex5 transcripts, suggesting that JMJD6 controls splicing of its own pre-mRNA. The distinct molecular properties of JMJD6-2 and JMJD6-Ex5 open a lead into the functional implications of the variations of their relative abundance in tumors.

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CTDP1 regulates breast cancer survival and DNA repair through BRCT-specific interactions with FANCI

Cited by 15 publications

References 62 publications

ATR-Mediated FANCI Phosphorylation Regulates Both Ubiquitination and Deubiquitination of FANCD2

ATR-Mediated FANCI Phosphorylation Regulates Both Ubiquitination and Deubiquitination of FANCD2

The Proteomic Landscape of Pancreatic Ductal Adenocarcinoma Liver Metastases Identifies Molecular Subtypes and Associations with Clinical Response

JMJD6 Regulates Splicing of Its Own Gene Resulting in Alternatively Spliced Isoforms with Different Nuclear Targets

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