Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10265)
Regulator Name Protein mono-ADP-ribosyltransferase PARP9 (PARP9)
Synonyms
ADP-ribosyltransferase diphtheria toxin-like 9; B aggressive lymphoma protein; Poly [ADP-ribose] polymerase 9
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Gene Name PARP9
Gene ID 83666
Regulator Type Protein coding
Uniprot ID Q8IXQ6
Sequence
MDFSMVAGAAAYNEKSGRITSLSLLFQKVFAQIFPQWRKGNTEECLPYKCSETGALGENY
SWQIPINHNDFKILKNNERQLCEVLQNKFGCISTLVSPVQEGNSKSLQVFRKMLTPRIEL
SVWKDDLTTHAVDAVVNAANEDLLHGGGLALALVKAGGFEIQEESKQFVARYGKVSAGEI
AVTGAGRLPCKQIIHAVGPRWMEWDKQGCTGKLQRAIVSILNYVIYKNTHIKTVAIPALS
SGIFQFPLNLCTKTIVETIRVSLQGKPMMSNLKEIHLVSNEDPTVAAFKAASEFILGKSE
LGQETTPSFNAMVVNNLTLQIVQGHIEWQTADVIVNSVNPHDITVGPVAKSILQQAGVEM
KSEFLATKAKQFQRSQLVLVTKGFNLFCKYIYHVLWHSEFPKPQILKHAMKECLEKCIEQ
NITSISFPALGTGNMEIKKETAAEILFDEVLTFAKDHVKHQLTVKFVIFPTDLEIYKAFS
SEMAKRSKMLSLNNYSVPQSTREEKRENGLEARSPAINLMGFNVEEMYEAHAWIQRILSL
QNHHIIENNHILYLGRKEHDILSQLQKTSSVSITEIISPGRTELEIEGARADLIEVVMNI
EDMLCKVQEEMARKKERGLWRSLGQWTIQQQKTQDEMKENIIFLKCPVPPTQELLDQKKQ
FEKCGLQVLKVEKIDNEVLMAAFQRKKKMMEEKLHRQPVSHRLFQQVPYQFCNVVCRVGF
QRMYSTPCDPKYGAGIYFTKNLKNLAEKAKKISAADKLIYVFEAEVLTGFFCQGHPLNIV
PPPLSPGAIDGHDSVVDNVSSPETFVIFSGMQAIPQYLWTCTQEYVQSQDYSSGPMRPFA
QHPWRGFASGSPVD

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Family ARTD/PARP family
Function
ADP-ribosyltransferase which, in association with E3 ligase DTX3L, plays a role in DNA damage repair and in immune responses including interferon-mediated antiviral defenses. Within the complex, enhances DTX3L E3 ligase activity which is further enhanced by PARP9 binding to poly(ADP-ribose). In association with DTX3L and in presence of E1 and E2 enzymes, mediates NAD(+)-dependent mono-ADP-ribosylation of ubiquitin which prevents ubiquitin conjugation to substrates such as histones. During DNA repair, PARP1 recruits PARP9/BAL1-DTX3L complex to DNA damage sites via PARP9 binding to ribosylated PARP1. Subsequent PARP1- dependent PARP9/BAL1-DTX3L-mediated ubiquitination promotes the rapid and specific recruitment of 53BP1/TP53BP1, UIMC1/RAP80, and BRCA1 to DNA damage sites. In response to DNA damage, PARP9-DTX3L complex is required for efficient non-homologous end joining (NHEJ); the complex function is negatively modulated by PARP9 activity. Dispensable for B-cell receptor (BCR) assembly through V(D)J recombination and class switch recombination (CSR). In macrophages, positively regulates pro- inflammatory cytokines production in response to IFNG stimulation by suppressing PARP14-mediated STAT1 ADP-ribosylation and thus promoting STAT1 phosphorylation. Also suppresses PARP14- mediated STAT6 ADP-ribosylation.

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HGNC ID
HGNC:24118
KEGG ID hsa:83666
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
PARP9 can regulate the following target(s), and cause disease/drug response(s). You can browse detail information of target(s) or disease/drug response(s).
Browse Target
Browse Disease
Cystine/glutamate transporter (SLC7A11) [Driver; Suppressor]
 Target Info 
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Suppressor
Responsed Disease Ovarian cancer ICD-11: 2C73
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
Cell apoptosis
In Vitro Model
 HEY cells Ovarian carcinoma Homo sapiens CVCL_0297
A2780 cells Ovarian endometrioid adenocarcinoma Homo sapiens CVCL_0134
SK-OV-3 cells Ovarian serous cystadenocarcinoma Homo sapiens CVCL_0532
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
Female 4- to 6-week-old BALB/c nude mice were purchased from SLA Laboratory Animal (Changsha, China) and housed in a specific pathogen-free facility. 2 x 106 A2780 or 1 x 106 HEY cells were injected subcutaneously into mice to grow tumors up to approximately 100 mm3. Mice were then intraperitoneally injected olaparib (100 mg/kg) or/and liproxstatin-1 (10 mg/kg, A2780) or/and sulfasalazine (250 mg/kg, HEY) until the endpoint indicated in the corresponding figures.

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Response regulation Mechanistically, pharmacological inhibition or genetic deletion of PARP9 downregulates the expression of cystine transporter SLC7A11 in a p53-dependent manner. Consequently, decreased glutathione biosynthesis caused by SLC7A11 repression promotes lipid peroxidation and ferroptosis. Pharmacologic inhibition of PARP9 is the primary therapeutic strategy for BRCA mutant ovarian cancer.
Ovarian cancer [ICD-11: 2C73]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator Protein mono-ADP-ribosyltransferase PARP9 (PARP9) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
Cell apoptosis
In Vitro Model
 HEY cells Ovarian carcinoma Homo sapiens CVCL_0297
A2780 cells Ovarian endometrioid adenocarcinoma Homo sapiens CVCL_0134
SK-OV-3 cells Ovarian serous cystadenocarcinoma Homo sapiens CVCL_0532
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
Female 4- to 6-week-old BALB/c nude mice were purchased from SLA Laboratory Animal (Changsha, China) and housed in a specific pathogen-free facility. 2 x 106 A2780 or 1 x 106 HEY cells were injected subcutaneously into mice to grow tumors up to approximately 100 mm3. Mice were then intraperitoneally injected olaparib (100 mg/kg) or/and liproxstatin-1 (10 mg/kg, A2780) or/and sulfasalazine (250 mg/kg, HEY) until the endpoint indicated in the corresponding figures.

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Response regulation Mechanistically, pharmacological inhibition or genetic deletion of PARP9 downregulates the expression of cystine transporter SLC7A11 in a p53-dependent manner. Consequently, decreased glutathione biosynthesis caused by SLC7A11 repression promotes lipid peroxidation and ferroptosis. Pharmacologic inhibition of PARP9 is the primary therapeutic strategy for BRCA mutant ovarian cancer.
References
Ref 1 PARP inhibition promotes ferroptosis via repressing SLC7A11 and synergizes with ferroptosis inducers in BRCA-proficient ovarian cancer. Redox Biol. 2021 Jun;42:101928. doi: 10.1016/j.redox.2021.101928. Epub 2021 Mar 5.