PMADS

Id:	acc0514
Group:	2sens
Protein:	DNMT1
Gene Symbol:	DNMT1
Protein Id:	P26358
Protein Name:	DNMT1_HUMAN
PTM:	ubiquitination
Site:	unclear
Site Sequence:
Disease Category:	Cancer
Disease:	Colorectal Cancer
Disease Subtype:
Disease Cellline:	HCT-8-7T
Disease Info:
Drug:	alisertib
Drug Info:	"Alisertib is a selective Aurora A kinase inhibitor investigated as an antineoplastic agent for the treatment of cancers with dysregulated mitotic processes, such as lymphomas and solid tumors."
Effect:	modulate
Effect Info:	"Alisertib promotes the ubiquitination and degradation of DNMT1, leading to the demethylation and overexpression of STAT1, which in turn causes tumor cells to develop resistance to alisertib."
Note:
Score:	4.0
Pubmed(PMID):	34522170
Sentence Index:	34522170_3-4
Sentence:	"Here, we found that signal transducer and activator of transcription 1 (STAT1) was highly expressed in colorectal cancer (CRC) xenograft mouse models that were resistant to alisertib, an Aurora-A inhibitor. Unexpectedly, we found that alisertib disrupted Aurora-A binding with ubiquitin-like with plant homeodomain and ring finger domain 1 (UHRF1), leading to UHRF1 mediated ubiquitination and degradation of DNA methyltransferase 1 (DNMT1), which in turn resulted in demethylation of CpG islands of STAT1 promoter and STAT1 overexpression."

Sequence & Structure:

MPARTAPARVPTLAVPAISLPDDVRRRLKDLERDSLTEKECVKEKLNLLHEFLQTEIKNQLCDLETKLRKEELSEEGYLAKVKSLLNKDLSLENGAHAYNREVNGRLENGNQARSEARRVGMADANSPPKPLSKPRTPRRSKSDGEAKPEPSPSPRITRKSTRQTTITSHFAKGPAKRKPQEESERAKSDESIKEEDKDQDEKRRRVTSRERVARPLPAEEPERAKSGTRTEKEEERDEKEEKRLRSQTKEPTPKQKLKEEPDREARAGVQADEDEDGDEKDEKKHRSQPKDLAAKRRPEEKEPEKVNPQISDEKDEDEKEEKRRKTTPKEPTEKKMARAKTVMNSKTHPPKCIQCGQYLDDPDLKYGQHPPDAVDEPQMLTNEKLSIFDANESGFESYEALPQHKLTCFSVYCKHGHLCPIDTGLIEKNIELFFSGSAKPIYDDDPSLEGGVNGKNLGPINEWWITGFDGGEKALIGFSTSFAEYILMDPSPEYAPIFGLMQEKIYISKIVVEFLQSNSDSTYEDLINKIETTVPPSGLNLNRFTEDSLLRHAQFVVEQVESYDEAGDSDEQPIFLTPCMRDLIKLAGVTLGQRRAQARRQTIRHSTREKDRGPTKATTTKLVYQIFDTFFAEQIEKDDREDKENAFKRRRCGVCEVCQQPECGKCKACKDMVKFGGSGRSKQACQERRCPNMAMKEADDDEEVDDNIPEMPSPKKMHQGKKKKQNKNRISWVGEAVKTDGKKSYYKKVCIDAETLEVGDCVSVIPDDSSKPLYLARVTALWEDSSNGQMFHAHWFCAGTDTVLGATSDPLELFLVDECEDMQLSYIHSKVKVIYKAPSENWAMEGGMDPESLLEGDDGKTYFYQLWYDQDYARFESPPKTQPTEDNKFKFCVSCARLAEMRQKEIPRVLEQLEDLDSRVLYYSATKNGILYRVGDGVYLPPEAFTFNIKLSSPVKRPRKEPVDEDLYPEHYRKYSDYIKGSNLDAPEPYRIGRIKEIFCPKKSNGRPNETDIKIRVNKFYRPENTHKSTPASYHADINLLYWSDEEAVVDFKAVQGRCTVEYGEDLPECVQVYSMGGPNRFYFLEAYNAKSKSFEDPPNHARSPGNKGKGKGKGKGKPKSQACEPSEPEIEIKLPKLRTLDVFSGCGGLSEGFHQAGISDTLWAIEMWDPAAQAFRLNNPGSTVFTEDCNILLKLVMAGETTNSRGQRLPQKGDVEMLCGGPPCQGFSGMNRFNSRTYSKFKNSLVVSFLSYCDYYRPRFFLLENVRNFVSFKRSMVLKLTLRCLVRMGYQCTFGVLQAGQYGVAQTRRRAIILAAAPGEKLPLFPEPLHVFAPRACQLSVVVDDKKFVSNITRLSSGPFRTITVRDTMSDLPEVRNGASALEISYNGEPQSWFQRQLRGAQYQPILRDHICKDMSALVAARMRHIPLAPGSDWRDLPNIEVRLSDGTMARKLRYTHHDRKNGRSSSGALRGVCSCVEAGKACDPAARQFNTLIPWCLPHTGNRHNHWAGLYGRLEWDGFFSTTVTNPEPMGKQGRVLHPEQHRVVSVRECARSQGFPDTYRLFGNILDKHRQVGNAVPPPLAKAIGLEIKLCMLAKARESASAKIKEEEAAKD

Select PDB:

Known Drugs:

source: Multi-Sources

(see table)

Target	Drug name	MOA	Phase	Status	Disease	Source
DNMT1	DECITABINE	DNA (cytosine-5)-methyltransferase 1 inhibitor	4	-	myelodysplastic syndrome	DailyMed DailyMed DailyMed DailyMed DailyMed DailyMed DailyMed DailyMed
DNMT1	DECITABINE	DNA (cytosine-5)-methyltransferase 1 inhibitor	4	Terminated	myelodysplastic syndrome	ClinicalTrials
DNMT1	AZACITIDINE	DNA (cytosine-5)-methyltransferase 1 inhibitor	4	Terminated	myelodysplastic syndrome	ClinicalTrials
DNMT1	DECITABINE	DNA (cytosine-5)-methyltransferase 1 inhibitor	4	Unknown status	myelodysplastic syndrome	ClinicalTrials ClinicalTrials
DNMT1	AZACITIDINE	DNA (cytosine-5)-methyltransferase 1 inhibitor	4	-	myelodysplastic syndrome	DailyMed DailyMed DailyMed EMA DailyMed DailyMed
DNMT1	AZACITIDINE	DNA (cytosine-5)-methyltransferase 1 inhibitor	4	Completed	myelodysplastic syndrome	ClinicalTrials
DNMT1	AZACITIDINE	DNA (cytosine-5)-methyltransferase 1 inhibitor	4	Not yet recruiting	myelodysplastic syndrome	ClinicalTrials
DNMT1	AZACITIDINE	DNA (cytosine-5)-methyltransferase 1 inhibitor	4	-	acute myeloid leukemia	EMA
DNMT1	AZACITIDINE	DNA (cytosine-5)-methyltransferase 1 inhibitor	4	Not yet recruiting	acute myeloid leukemia	ClinicalTrials
DNMT1	DECITABINE	DNA (cytosine-5)-methyltransferase 1 inhibitor	4	-	neoplasm	ATC
DNMT1	AZACITIDINE	DNA (cytosine-5)-methyltransferase 1 inhibitor	4	-	neoplasm	ATC
DNMT1	DECITABINE	DNA (cytosine-5)-methyltransferase 1 inhibitor	4	-	refractory anemia with excess blasts	DailyMed DailyMed DailyMed DailyMed DailyMed DailyMed DailyMed
DNMT1	AZACITIDINE	DNA (cytosine-5)-methyltransferase 1 inhibitor	4	-	refractory anemia with excess blasts	DailyMed DailyMed DailyMed DailyMed DailyMed
DNMT1	DECITABINE	DNA (cytosine-5)-methyltransferase 1 inhibitor	4	-	chronic myelomonocytic leukemia	DailyMed DailyMed DailyMed DailyMed DailyMed DailyMed DailyMed
DNMT1	AZACITIDINE	DNA (cytosine-5)-methyltransferase 1 inhibitor	4	-	chronic myelomonocytic leukemia	EMA DailyMed DailyMed DailyMed DailyMed DailyMed
DNMT1	AZACITIDINE	DNA (cytosine-5)-methyltransferase 1 inhibitor	4	-	Thrombocytopenia	DailyMed
DNMT1	DECITABINE	DNA (cytosine-5)-methyltransferase 1 inhibitor	4	-	anemia	DailyMed DailyMed
DNMT1	AZACITIDINE	DNA (cytosine-5)-methyltransferase 1 inhibitor	4	-	anemia	DailyMed
DNMT1	DECITABINE	DNA (cytosine-5)-methyltransferase 1 inhibitor	4	-	myeloid leukemia	EMA
DNMT1	DECITABINE	DNA (cytosine-5)-methyltransferase 1 inhibitor	3	Unknown status	myelodysplastic syndrome	ClinicalTrials
DNMT1	DECITABINE	DNA (cytosine-5)-methyltransferase 1 inhibitor	3	Withdrawn	myelodysplastic syndrome	ClinicalTrials
DNMT1	AZACITIDINE	DNA (cytosine-5)-methyltransferase 1 inhibitor	3	Not yet recruiting	myelodysplastic syndrome	ClinicalTrials
DNMT1	AZACITIDINE	DNA (cytosine-5)-methyltransferase 1 inhibitor	3	Terminated	myelodysplastic syndrome	ClinicalTrials
DNMT1	DECITABINE	DNA (cytosine-5)-methyltransferase 1 inhibitor	3	Completed	myelodysplastic syndrome	ClinicalTrials ClinicalTrials ClinicalTrials ClinicalTrials
DNMT1	DECITABINE	DNA (cytosine-5)-methyltransferase 1 inhibitor	3	Not yet recruiting	unspecified peripheral T-cell lymphoma	ClinicalTrials

Note: Only show clinically investigational or approved drugs with protein targets.

Protein Tractability:

source: Open Targets

Small molecule

Antibody

PROTAC

Other modalities

Approved Drug

Advanced Clinical

Phase 1 Clinical

Structure with Ligand

High-Quality Ligand

High-Quality Pocket

Med-Quality Pocket

Druggable Family

Approved Drug

Advanced Clinical

Phase 1 Clinical

UniProt loc high conf

GO CC high conf

UniProt loc med conf

UniProt SigP or TMHMM

GO CC med conf

Human Protein Atlas loc

Approved Drug

Advanced Clinical

Phase 1 Clinical

Literature

UniProt Ubiquitination

Database Ubiquitination

Half-life Data

Small Molecule Binder

Approved Drug

Advanced Clinical

Phase 1 Clinical

PTM Intensity:

source: CPTAC

No data.

PTM-Disease Association:

source: PTMD

Residue	Position	State	Disease	Class	PMID
-	-	D	Gastric cancer	Ubiquitination	37147733
-	-	U	Heart failure	Acetylation	33932446

State Note: Based on the distinct PTM states in diseases, PTMD classified all disease-associated PTMs into six classes, including whether the up-regulation (U) or down-regulation (D) of PTM levels, the absence (A) or presence (P) of PTMs, and the creation (C) or disruption (N) of PTM sites are associated with diseases.

PTM-Drug Perturbation Response:

source: DecryptM

No data.

Function score:

source: funscoR

No data.

Cross Links:

CTD
DMRdb