Molecule Information

General Information of the Molecule (ID: Mol04171)

• Name: X-ray repair cross-complementing protein 1 (XRCC1) ,Homo sapiens
• Synonyms: X-ray repair cross-complementing protein 1
• Molecule Type: Protein
• Gene Name: XRCC1
• Gene ID: 7515
• Location: chr19:43543311-43580473[-]
• Sequence:
  MPEIRLRHVVSCSSQDSTHCAENLLKADTYRKWRAAKAGEKTISVVLQLEKEEQIHSVDI
  GNDGSAFVEVLVGSSAGGAGEQDYEVLLVTSSFMSPSESRSGSNPNRVRMFGPDKLVRAA
  AEKRWDRVKIVCSQPYSKDSPFGLSFVRFHSPPDKDEAEAPSQKVTVTKLGQFRVKEEDE
  SANSLRPGALFFSRINKTSPVTASDPAGPSYAAATLQASSAASSASPVSRAIGSTSKPQE
  SPKGKRKLDLNQEEKKTPSKPPAQLSPSVPKRPKLPAPTRTPATAPVPARAQGAVTGKPR
  GEGTEPRRPRAGPEELGKILQGVVVVLSGFQNPFRSELRDKALELGAKYRPDWTRDSTHL
  ICAFANTPKYSQVLGLGGRIVRKEWVLDCHRMRRRLPSQRYLMAGPGSSSEEDEASHSGG
  SGDEAPKLPQKQPQTKTKPTQAAGPSSPQKPPTPEETKAASPVLQEDIDIEGVQSEGQDN
  GAEDSGDTEDELRRVAEQKEHRLPPGQEENGEDPYAGSTDENTDSEEHQEPPDLPVPELP
  DFFQGKHFFLYGEFPGDERRKLIRYVTAFNGELEDYMSDRVQFVITAQEWDPSFEEALMD
  NPSLAFVRPRWIYSCNEKQKLLPHQLYGVVPQA
• 3D-structure: PDB ID: 3LQC; Classification: Dna binding protein; Method: X-ray diffraction; Resolution: 2.35 Å
• Function: Scaffold protein involved in DNA single-strand break repair by mediating the assembly of DNA break repair protein complexes (PubMed:11163244, PubMed:28002403). Negatively regulates ADP- ribosyltransferase activity of PARP1 during base-excision repair in order to prevent excessive PARP1 activity (PubMed:28002403, PubMed:34102106, PubMed:34811483). Recognizes and binds poly-ADP-ribose chains: specifically binds auto-poly-ADP-ribosylated PARP1, limiting its activity (PubMed:14500814, PubMed:34102106, PubMed:34811483). .
• Uniprot ID: XRCC1_HUMAN
• Ensembl ID: ENSG00000073050
• HGNC ID: HGNC:12828

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

Type(s) of Resistant Mechanism of This Molecule

  MRAP: Metabolic Reprogramming via Altered Pathways

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Temozolomide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Aldh1a3-overexpressing glioblastoma [ICD-11: 2A00.0] [2]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Aldh1a3-overexpressing glioblastoma [ICD-11: 2A00.0]
• Resistant Drug: Temozolomide
• Molecule Alteration: Lactylation; K247
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: Patients with GBM; Homo Sapiens
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Survival after radiochemotherapy assay
• Mechanism Description: ALDH1A3-mediated tetramerization of PKM2 induces glycometabolic reprogramming in GSCs. Accumulation of lactate increases the lactylation of the K247 site on XRCC1. The lactylation of XRCC1 improves DNA repair via its increased nuclear localization. By blocking PKM2, D34-919 restores sensitivity to chemoradiotherapy for GBMs

Disease Class: Aldh1a3-overexpressing glioblastoma [ICD-11: 2A00.0] [2]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Aldh1a3-overexpressing glioblastoma [ICD-11: 2A00.0]
• Resistant Drug: Temozolomide
• Molecule Alteration: Lactylation; K247
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Rescue cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: ALDH1A3-mediated tetramerization of PKM2 induces glycometabolic reprogramming in GSCs. Accumulation of lactate increases the lactylation of the K247 site on XRCC1. The lactylation of XRCC1 improves DNA repair via its increased nuclear localization. By blocking PKM2, D34-919 restores sensitivity to chemoradiotherapy for GBMs

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Aldh1a3-overexpressing glioblastoma [ICD-11: 2A00.0] [2]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Aldh1a3-overexpressing glioblastoma [ICD-11: 2A00.0]
• Sensitive Drug: Temozolomide
• Molecule Alteration: Lactylation; K247
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: ALDH1A3 knockout cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: ALDH1A3-mediated tetramerization of PKM2 induces glycometabolic reprogramming in GSCs. Accumulation of lactate increases the lactylation of the K247 site on XRCC1. The lactylation of XRCC1 improves DNA repair via its increased nuclear localization. By blocking PKM2, D34-919 restores sensitivity to chemoradiotherapy for GBMs

References

• Ref 1: Difluoromethylornithine (DFMO) Enhances the Cytotoxicity of PARP Inhibition in Ovarian Cancer Cells. Med Sci (Basel). 2022 May 26;10(2):28.
• Ref 2: Glycometabolic reprogramming-induced XRCC1 lactylation confers therapeutic resistance in ALDH1A3-overexpressing glioblastoma. Cell Metab. 2024 Aug 6;36(8):1696-1710.e10.