Molecule Information

General Information of the Molecule (ID: Mol00321)

• Name: DNA damage-binding protein 1 (DDB1) ,Homo sapiens
• Synonyms: DDB p127 subunit; DNA damage-binding protein a; DDBa; Damage-specific DNA-binding protein 1; HBV X-associated protein 1; XAP-1; UV-damaged DNA-binding factor; UV-damaged DNA-binding protein 1; UV-DDB 1; XPE-binding factor; XPE-BF; Xeroderma pigmentosum group E-complementing protein; XPCe; XAP1
• Molecule Type: Protein
• Gene Name: DDB1
• Gene ID: 1642
• Location: chr11:61299451-61342596[-]
• Sequence:
  MSYNYVVTAQKPTAVNGCVTGHFTSAEDLNLLIAKNTRLEIYVVTAEGLRPVKEVGMYGK
  IAVMELFRPKGESKDLLFILTAKYNACILEYKQSGESIDIITRAHGNVQDRIGRPSETGI
  IGIIDPECRMIGLRLYDGLFKVIPLDRDNKELKAFNIRLEELHVIDVKFLYGCQAPTICF
  VYQDPQGRHVKTYEVSLREKEFNKGPWKQENVEAEASMVIAVPEPFGGAIIIGQESITYH
  NGDKYLAIAPPIIKQSTIVCHNRVDPNGSRYLLGDMEGRLFMLLLEKEEQMDGTVTLKDL
  RVELLGETSIAECLTYLDNGVVFVGSRLGDSQLVKLNVDSNEQGSYVVAMETFTNLGPIV
  DMCVVDLERQGQGQLVTCSGAFKEGSLRIIRNGIGIHEHASIDLPGIKGLWPLRSDPNRE
  TDDTLVLSFVGQTRVLMLNGEEVEETELMGFVDDQQTFFCGNVAHQQLIQITSASVRLVS
  QEPKALVSEWKEPQAKNISVASCNSSQVVVAVGRALYYLQIHPQELRQISHTEMEHEVAC
  LDITPLGDSNGLSPLCAIGLWTDISARILKLPSFELLHKEMLGGEIIPRSILMTTFESSH
  YLLCALGDGALFYFGLNIETGLLSDRKKVTLGTQPTVLRTFRSLSTTNVFACSDRPTVIY
  SSNHKLVFSNVNLKEVNYMCPLNSDGYPDSLALANNSTLTIGTIDEIQKLHIRTVPLYES
  PRKICYQEVSQCFGVLSSRIEVQDTSGGTTALRPSASTQALSSSVSSSKLFSSSTAPHET
  SFGEEVEVHNLLIIDQHTFEVLHAHQFLQNEYALSLVSCKLGKDPNTYFIVGTAMVYPEE
  AEPKQGRIVVFQYSDGKLQTVAEKEVKGAVYSMVEFNGKLLASINSTVRLYEWTTEKELR
  TECNHYNNIMALYLKTKGDFILVGDLMRSVLLLAYKPMEGNFEEIARDFNPNWMSAVEIL
  DDDNFLGAENAFNLFVCQKDSAATTDEERQHLQEVGLFHLGEFVNVFCHGSLVMQNLGET
  STPTQGSVLFGTVNGMIGLVTSLSESWYNLLLDMQNRLNKVIKSVGKIEHSFWRSFHTER
  KTEPATGFIDGDLIESFLDISRPKMQEVVANLQYDDGSGMKREATADDLIKVVEELTRIH
• Function: Protein, which is both involved in DNA repair and protein ubiquitination, as part of the UV-DDB complex and DCX (DDB1-CUL4-X-box) complexes, respectively. Core component of the UV-DDB complex (UV-damaged DNA-binding protein complex), a complex that recognizes UV-induced DNA damage and recruit proteins of the nucleotide excision repair pathway (the NER pathway) to initiate DNA repair. The UV-DDB complex preferentially binds to cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (6-4 PP), apurinic sites and short mismatches. Also functions as a component of numerous distinct DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. The functional specificity of the DCX E3 ubiquitin-protein ligase complex is determined by the variable substrate recognition component recruited by DDB1. DCX(DDB2) (also known as DDB1-CUL4-ROC1, CUL4-DDB-ROC1 and CUL4-DDB-RBX1) may ubiquitinate histone H2A, histone H3 and histone H4 at sites of UV-induced DNA damage. The ubiquitination of histones may facilitate their removal from the nucleosome and promote subsequent DNA repair. DCX(DDB2) also ubiquitinates XPC, which may enhance DNA-binding by XPC and promote NER. DCX(DTL) plays a role in PCNA-dependent polyubiquitination of CDT1 and MDM2-dependent ubiquitination of TP53 in response to radiation-induced DNA damage and during DNA replication. DCX(ERCC8) (the CSA complex) plays a role in transcription-coupled repair (TCR). The DDB1-CUL4A-DTL E3 ligase complex regulates the circadian clock function by mediating the ubiquitination and degradation of CRY1. DDB1-mediated CRY1 degradation promotes FOXO1 protein stability and FOXO1-mediated gluconeogenesis in the liver.
• Uniprot ID: DDB1_HUMAN
• Ensembl ID: ENSG00000167986
• HGNC ID: HGNC:2717

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Lenalidomide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Multiple myeloma [1]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Resistant Drug: Lenalidomide
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/RAS signaling pathway; Regulation; hsa04151
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
• Experiment for Drug Resistance: Longitudinal copy number aberration (CNA) analysis
• Mechanism Description: Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Thalidomide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Multiple myeloma [1]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Resistant Drug: Thalidomide
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/RAS signaling pathway; Regulation; hsa04151
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
• Experiment for Drug Resistance: Longitudinal copy number aberration (CNA) analysis
• Mechanism Description: Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Multiple myeloma [ICD-11: 2A83]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Bone marrow
• The Specified Disease: Multiple myeloma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.44E-03; Fold-change: 6.89E-01; Z-score: 1.89E+00
• The Studied Tissue: Peripheral blood
• The Specified Disease: Multiple myeloma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.30E-01; Fold-change: -6.76E-02; Z-score: -1.63E-01

References

• Ref 1: Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma. Blood. 2016 Sep 29;128(13):1735-44. doi: 10.1182/blood-2016-06-723007. Epub 2016 Aug 11.