Molecule Information

General Information of the Molecule (ID: Mol04135)

• Name: Nijmegen breakage syndrome protein 1 (NBS1) ,Homo sapiens
• Synonyms: Cell cycle regulatory protein p95; Nijmegen breakage syndrome protein 1
• Molecule Type: Protein
• Gene Name: NBN
• Gene ID: 4683
• Location: chr8:89924515-90003228[-]
• Sequence:
  MWKLLPAAGPAGGEPYRLLTGVEYVVGRKNCAILIENDQSISRNHAVLTANFSVTNLSQT
  DEIPVLTLKDNSKYGTFVNEEKMQNGFSRTLKSGDGITFGVFGSKFRIEYEPLVACSSCL
  DVSGKTALNQAILQLGGFTVNNWTEECTHLVMVSVKVTIKTICALICGRPIVKPEYFTEF
  LKAVESKKQPPQIESFYPPLDEPSIGSKNVDLSGRQERKQIFKGKTFIFLNAKQHKKLSS
  AVVFGGGEARLITEENEEEHNFFLAPGTCVVDTGITNSQTLIPDCQKKWIQSIMDMLQRQ
  GLRPIPEAEIGLAVIFMTTKNYCDPQGHPSTGLKTTTPGPSLSQGVSVDEKLMPSAPVNT
  TTYVADTESEQADTWDLSERPKEIKVSKMEQKFRMLSQDAPTVKESCKTSSNNNSMVSNT
  LAKMRIPNYQLSPTKLPSINKSKDRASQQQQTNSIRNYFQPSTKKRERDEENQEMSSCKS
  ARIETSCSLLEQTQPATPSLWKNKEQHLSENEPVDTNSDNNLFTDTDLKSIVKNSASKSH
  AAEKLRSNKKREMDDVAIEDEVLEQLFKDTKPELEIDVKVQKQEEDVNVRKRPRMDIETN
  DTFSDEAVPESSKISQENEIGKKRELKEDSLWSAKEISNNDKLQDDSEMLPKKLLLTEFR
  SLVIKNSTSRNPSGINDDYGQLKNFKKFKKVTYPGAGKLPHIIGGSDLIAHHARKNTELE
  EWLRQEMEVQNQHAKEESLADDLFRYNPYLKRRR
• 3D-structure: PDB ID: 5WQD; Classification: Cell cycle; Method: X-ray diffraction; Resolution: 3.00 Å
• Function: Component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis (PubMed:10888888, PubMed:15616588, PubMed:18411307, PubMed:18583988, PubMed:18678890, PubMed:19759395, PubMed:23115235, PubMed:28216226, PubMed:28867292, PubMed:9705271). The MRN complex is involved in the repair of DNA double-strand breaks (DSBs) via homologous recombination (HR), an error-free mechanism which primarily occurs during S and G2 phases (PubMed:19759395, PubMed:28867292, PubMed:9705271). The complex (1) mediates the end resection of damaged DNA, which generates proper single-stranded DNA, a key initial steps in HR, and is (2) required for the recruitment of other repair factors and efficient activation of ATM and ATR upon DNA damage (PubMed:19759395, PubMed:9705271). The MRN complex possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity, which are provided by MRE11, to initiate end resection, which is required for single-strand invasion and recombination (PubMed:19759395, PubMed:28867292, PubMed:9705271). Within the MRN complex, NBN acts as a protein-protein adapter, which specifically recognizes and binds phosphorylated proteins, promoting their recruitment to DNA damage sites (PubMed:12419185, PubMed:15616588, PubMed:18411307, PubMed:18582474, PubMed:18583988, PubMed:18678890, PubMed:19759395, PubMed:19804756, PubMed:23762398, PubMed:24534091, PubMed:27814491, PubMed:27889449, PubMed:33836577). Recruits MRE11 and RAD50 components of the MRN complex to DSBs in response to DNA damage (PubMed:12419185, PubMed:18411307, PubMed:18583988, PubMed:18678890, PubMed:24534091, PubMed:26438602). Promotes the recruitment of PI3/PI4-kinase family members ATM, ATR, and probably DNA-PKcs to the DNA damage sites, activating their functions (PubMed:15064416, PubMed:15616588, PubMed:15790808, PubMed:16622404, PubMed:22464731, PubMed:30952868, PubMed:35076389). Mediates the recruitment of phosphorylated RBBP8/CtIP to DSBs, leading to cooperation between the MRN complex and RBBP8/CtIP to initiate end resection (PubMed:19759395, PubMed:27814491, PubMed:27889449, PubMed:33836577). RBBP8/CtIP specifically promotes the endonuclease activity of the MRN complex to clear DNA ends containing protein adducts (PubMed:27814491, PubMed:27889449, PubMed:30787182, PubMed:33836577). The MRN complex is also required for the processing of R-loops (PubMed:31537797). NBN also functions in telomere length maintenance via its interaction with TERF2: interaction with TERF2 during G1 phase preventing recruitment of DCLRE1B/Apollo to telomeres (PubMed:10888888, PubMed:28216226). NBN also promotes DNA repair choice at dysfunctional telomeres: NBN phosphorylation by CK2 promotes non- homologous end joining repair at telomeres, while unphosphorylated NBN promotes microhomology-mediated end-joining (MMEJ) repair (PubMed:28216226). Enhances AKT1 phosphorylation possibly by association with the mTORC2 complex (PubMed:23762398). .
• Uniprot ID: NBN_HUMAN
• Ensembl ID: ENSG00000104320
• HGNC ID: HGNC:7652

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

Drug Resistance Data Categorized by Drug

Approved Drug(s) 3 drug(s) in total

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Gastric adenocarcinoma [ICD-11: 2B72.0] [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Lactylation; K388
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: MGC83-P cells; Stomach; Homo sapiens (Human); CVCL_5334
• In Vivo Model: NSG mice bearing MGC803-P xenografts; mice with patient-derived xenografts (PDXs) derived from two cases of gastric cancer; Mice
• Experiment for Molecule Alteration: LC-MS/MS analysis
• Mechanism Description: Lactylation of NBS1 at lysine 388 (K388) is essential for MRE11-RAD50-NBS1 (MRN) complex formation and the accumulation of HR repair proteins at the sites of DNA double-strand breaks.It promotes DNA-damaging treatment resistance via HR repair.

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Lactylation; K388
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: LC-MS/MS analysis
• Mechanism Description: Lactylation of NBS1 at lysine 388 (K388) is essential for MRE11-RAD50-NBS1 (MRN) complex formation and the accumulation of HR repair proteins at the sites of DNA double-strand breaks.It promotes DNA-damaging treatment resistance via HR repair.

Daunorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Gastric adenocarcinoma [ICD-11: 2B72.0] [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Resistant Drug: Daunorubicin
• Molecule Alteration: Lactylation; K388
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• Experiment for Molecule Alteration: LC-MS/MS analysis
• Mechanism Description: Lactylation of NBS1 at lysine 388 (K388) is essential for MRE11-RAD50-NBS1 (MRN) complex formation and the accumulation of HR repair proteins at the sites of DNA double-strand breaks.It promotes DNA-damaging treatment resistance via HR repair.

Etoposide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Gastric adenocarcinoma [ICD-11: 2B72.0] [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Resistant Drug: Etoposide
• Molecule Alteration: Lactylation; K388
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• Experiment for Molecule Alteration: LC-MS/MS analysis
• Mechanism Description: Lactylation of NBS1 at lysine 388 (K388) is essential for MRE11-RAD50-NBS1 (MRN) complex formation and the accumulation of HR repair proteins at the sites of DNA double-strand breaks.It promotes DNA-damaging treatment resistance via HR repair.

References

• Ref 1: NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance. Nature. 2024 Jul;631(8021):663-669.