Annotation inferences using phylogenetic trees

Gene Ontology annotation based on UniPathway vocabulary mapping

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:16861906

L2DTL/CDT2 interacts with the CUL4/DDB1 complex and PCNA and regulates CDT1 proteolysis in response to DNA damage.

L2DTL/CDT2 is a conserved WD40 protein that associates with CUL4/DDB1 and PCNA and is required for CDT1 proteolysis after DNA damage.

PMID:16949367

A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1.

Cdt2 is a DCAF (DDB1-CUL4-associated factor) substrate receptor required to destroy Cdt1 in S phase and after DNA damage; depletion causes rereplication and checkpoint activation.

PMID:17041588

CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins and regulates histone methylation.

CUL4-DDB1 interacts with multiple WD40-repeat proteins including L2DTL/CDT2, which regulates CDT1 proteolysis through CUL4-DDB1.

PMID:17085480

DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint.

DTL promotes genomic stability by two mechanisms - as a CUL4-DDB1 component controlling CDT1 levels (preventing rereplication) and as an essential component of the early radiation-induced G2/M checkpoint (CDT1-independent).

PMID:17106265

Role of L2DTL, cell cycle-regulated nuclear and centrosome protein, in aggressive hepatocellular carcinoma.

L2DTL localizes to the nucleus in interphase and to centrosomes through the cell cycle, is degraded in mitosis by APC/C-Cdh1, and is overexpressed in aggressive HCC.

PMID:18794347

PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex.

PCNA promotes CRL4(Cdt2)-mediated ubiquitylation and UV-induced degradation of p21; Cdt2 is the substrate-recruiting factor and the complex ubiquitylates p21 in vivo and in vitro.

PMID:20129063

CRL4(Cdt2) E3 ubiquitin ligase monoubiquitinates PCNA to promote translesion DNA synthesis.

CRL4(Cdt2) monoubiquitinates PCNA at Lys164 in proliferating cells independent of Rad18 and is required for translesion DNA synthesis; antagonized by USP1.

PMID:21628527

Selective ubiquitylation of p21 and Cdt1 by UBCH8 and UBE2G ubiquitin-conjugating enzymes via the CRL4Cdt2 ubiquitin ligase complex.

CRL4(Cdt2) uses UBCH8 to degrade p21 and Set8 and monoubiquitinate PCNA, and UBE2G to polyubiquitinate Cdt1, demonstrating substrate-selective E2 usage.

PMID:23213251

TRIM39 regulates cell cycle progression and DNA damage responses via stabilizing p21.

TRIM39 stabilizes p21 and modulates G1/S and G2 checkpoints; DTL interacts with CDKN1A/p21.

PMID:26431207

CUL4-DDB1-CDT2 E3 Ligase Regulates the Molecular Clock Activity by Promoting Ubiquitination-Dependent Degradation of the Mammalian CRY1.

CUL4-DDB1-CDT2 ubiquitinates and degrades CRY1 (at Lys585); depletion of Cdt2/Ddb1/Pcna stabilizes CRY1 and alters circadian amplitude.

PMID:27906959

PCNA-Dependent Cleavage and Degradation of SDE2 Regulates Response to Replication Stress.

Cleaved SDE2 is degraded by CRL4(CDT2) in a cell-cycle- and DNA-damage-dependent manner; failure to degrade SDE2 impairs S-phase progression and survival.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

PMID:36931259

A central chaperone-like role for 14-3-3 proteins in human cells.

file:human/DTL/DTL-deep-research-falcon.md

Falcon deep research report for human DTL

DTL/CDT2 is the substrate-recognition (DCAF/adaptor) component of the CRL4(CDT2) CUL4-DDB1 E3 ligase that promotes substrate polyubiquitination and proteasomal degradation, central to S-phase control and genome maintenance; it is not the catalytic E3 itself.

"DTL is **not an enzyme that catalyzes a chemical transformation** (i.e., it is not the catalytic E3). Rather, its **primary biochemical function** is to act as the **adaptor/substrate receptor** that enables **CRL4-dependent ubiquitination** of selected proteins—particularly proteins that are engaged with PCNA on chromatin—thereby coupling replication/repair to proteostasis."
CRL4(CDT2) substrates are recruited via a PIP-degron (a PIP box plus an adjacent basic signature) on chromatin-bound PCNA, restricting ubiquitination to sites of DNA synthesis and repair synthesis.

"Canonical CRL4^CDT2 substrates contain a **PIP-degron**: a PCNA-interacting PIP motif plus an adjacent basic signature (often described as Arg/Lys residues downstream of the PIP box) that transforms PCNA binding into a degradation signal for CRL4^CDT2."
The best-established CRL4(CDT2) substrates are CDT1 (replication licensing), p21/CDKN1A (CDK inhibitor), and SET8/KMT5A (the sole H4K20 monomethyltransferase), the last linking DTL to chromatin regulation and replication-fork stability.

"SET8 is highlighted as the **sole H4K20 monomethyltransferase**, connecting DTL to chromatin regulation and replication-fork stability."
CRL4(CDT2) activity must be tuned at stalled replication forks; DCAF14 restrains CRL4(CDT2), and its loss causes excessive turnover of CDT2 substrates (SET8, CDT1, p21) and replication-stress phenotypes rescuable by CDT2 depletion.

"Loss of DCAF14 caused **increased turnover of CDT2 substrates** (SET8, CDT1, p21), reduced SET8-linked chromatin marks, and replication-stress phenotypes including **nascent strand degradation** and increased DNA breakage signals, which could be rescued by **CDT2 depletion** and by inhibitors of cullin activation (MLN4924) or the proteasome (MG132)."

Reactome:R-HSA-5652005

RAD18:UBE2B or RBX1:CUL4:DDB1:DTL ubiquitin ligase complex binds PCNA:POLD,POLE:RPA:RFC associated with damaged dsDNA

Reactome:R-HSA-5652009

RAD18:UBE2B or RBX1:CUL4:DDB1:DTL monoubiquitinates PCNA

Reactome:R-HSA-8952638

AcM-UBE2M transfers NEDD8 to CRL4 E3 ubiquitin ligase complex

Reactome:R-HSA-8952639

NEDD8:AcM-UBE2M binds CRL4 E3 ubiquitin ligase complex

Reactome:R-HSA-8955245

CAND1 binds CRL4 E3 ubiquitin ligase in the nucleus

Reactome:R-HSA-8955285

COMMDs displace CAND1 from CRL4 E3 ubiquitin ligase complex

Reactome:R-HSA-8956045

COP9 signalosome deneddylates nuclear CRL4 E3 ubiquitin ligase complex