Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6DNDBG)

• DOT Name: Partner and localizer of BRCA2 (PALB2)
• Gene Name: PALB2
• Related Disease:
  Adult lymphoma
  Familial prostate carcinoma
  Fanconi anemia complementation group N
  Gastric adenocarcinoma
  Hereditary breast carcinoma
  Invasive breast carcinoma
  Lymphoma
  Matthew-Wood syndrome
  Pediatric lymphoma
  Pure red-cell aplasia
  Stomach cancer
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Adenocarcinoma
  Beckwith-Wiedemann syndrome
  Bipolar disorder
  Breast neoplasm
  Head and neck cancer
  Head and neck carcinoma
  Hereditary diffuse gastric adenocarcinoma
  Lynch syndrome
  Malignant neoplasm
  Metastatic prostate carcinoma
  Myelodysplastic syndrome
  Non-small-cell lung cancer
  Pancreatic adenocarcinoma
  Pancreatic cancer, susceptibility to, 3
  Pancreatic ductal carcinoma
  Pancytopenia
  Familial adenomatous polyposis
  Familial ovarian cancer
  Neuroendocrine neoplasm
  Pancreatic tumour
  Triple negative breast cancer
  Fanconi's anemia
  Gastric cancer
  Hereditary neoplastic syndrome
  Breast disorder
  Fanconi anemia complementation group A
  Hereditary nonpolyposis colon cancer
  Lynch syndrome 1
  Lynch syndrome 2
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
• UniProt ID: PALB2_HUMAN
• PDB ID: 2W18; 3EU7; 7S4A
• Pfam ID: PF16756
• Sequence:
  MDEPPGKPLSCEEKEKLKEKLAFLKREYSKTLARLQRAQRAEKIKHSIKKTVEEQDCLSQ
  QDLSPQLKHSEPKNKICVYDKLHIKTHLDEETGEKTSITLDVGPESFNPGDGPGGLPIQR
  TDDTQEHFPHRVSDPSGEQKQKLPSRRKKQQKRTFISQERDCVFGTDSLRLSGKRLKEQE
  EISSKNPARSPVTEIRTHLLSLKSELPDSPEPVTEINEDSVLIPPTAQPEKGVDTFLRRP
  NFTRATTVPLQTLSDSGSSQHLEHIPPKGSSELTTHDLKNIRFTSPVSLEAQGKKMTVST
  DNLLVNKAISKSGQLPTSSNLEANISCSLNELTYNNLPANENQNLKEQNQTEKSLKSPSD
  TLDGRNENLQESEILSQPKSLSLEATSPLSAEKHSCTVPEGLLFPAEYYVRTTRSMSNCQ
  RKVAVEAVIQSHLDVKKKGFKNKNKDASKNLNLSNEETDQSEIRMSGTCTGQPSSRTSQK
  LLSLTKVSSPAGPTEDNDLSRKAVAQAPGRRYTGKRKSACTPASDHCEPLLPTSSLSIVN
  RSKEEVTSHKYQHEKLFIQVKGKKSRHQKEDSLSWSNSAYLSLDDDAFTAPFHRDGMLSL
  KQLLSFLSITDFQLPDEDFGPLKLEKVKSCSEKPVEPFESKMFGERHLKEGSCIFPEELS
  PKRMDTEMEDLEEDLIVLPGKSHPKRPNSQSQHTKTGLSSSILLYTPLNTVAPDDNDRPT
  TDMCSPAFPILGTTPAFGPQGSYEKASTEVAGRTCCTPQLAHLKDSVCLASDTKQFDSSG
  SPAKPHTTLQVSGRQGQPTCDCDSVPPGTPPPIESFTFKENQLCRNTCQELHKHSVEQTE
  TAELPASDSINPGNLQLVSELKNPSGSCSVDVSAMFWERAGCKEPCIITACEDVVSLWKA
  LDAWQWEKLYTWHFAEVPVLQIVPVPDVYNLVCVALGNLEIREIRALFCSSDDESEKQVL
  LKSGNIKAVLGLTKRRLVSSSGTLSDQQVEVMTFAEDGGGKENQFLMPPEETILTFAEVQ
  GMQEALLGTTIMNNIVIWNLKTGQLLKKMHIDDSYQASVCHKAYSEMGLLFIVLSHPCAK
  ESESLRSPVFQLIVINPKTTLSVGVMLYCLPPGQAGRFLEGDVKDHCAAAILTSGTIAIW
  DLLLGQCTALLPPVSDQHWSFVKWSGTDSHLLAGQKDGNIFVYHYS
• Function: Plays a critical role in homologous recombination repair (HRR) through its ability to recruit BRCA2 and RAD51 to DNA breaks. Strongly stimulates the DNA strand-invasion activity of RAD51, stabilizes the nucleoprotein filament against a disruptive BRC3-BRC4 polypeptide and helps RAD51 to overcome the suppressive effect of replication protein A (RPA). Functionally cooperates with RAD51AP1 in promoting of D-loop formation by RAD51. Serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex which is essential for homologous recombination. Via its WD repeats is proposed to scaffold a HR complex containing RAD51C and BRCA2 which is thought to play a role in HR-mediated DNA repair. Essential partner of BRCA2 that promotes the localization and stability of BRCA2. Also enables its recombinational repair and checkpoint functions of BRCA2. May act by promoting stable association of BRCA2 with nuclear structures, allowing BRCA2 to escape the effects of proteasome-mediated degradation. Binds DNA with high affinity for D loop, which comprises single-stranded, double-stranded and branched DNA structures. May play a role in the extension step after strand invasion at replication-dependent DNA double-strand breaks; together with BRCA2 is involved in both POLH localization at collapsed replication forks and DNA polymerization activity.
• KEGG Pathway:
  Homologous recombi.tion (hsa03440)
  Fanconi anemia pathway (hsa03460)
• Reactome Pathway:
  Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) (R-HSA-5693554)
  Resolution of D-loop Structures through Holliday Junction Intermediates (R-HSA-5693568)
  Homologous DNA Pairing and Strand Exchange (R-HSA-5693579)
  Neddylation (R-HSA-8951664)
  Defective homologous recombination repair (HRR) due to BRCA1 loss of function (R-HSA-9701192)
  Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function (R-HSA-9704331)
  Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function (R-HSA-9704646)
  Impaired BRCA2 binding to PALB2 (R-HSA-9709603)
  KEAP1-NFE2L2 pathway (R-HSA-9755511)
  HDR through Homologous Recombination (HRR) (R-HSA-5685942)

Molecular Interaction Atlas (MIA) of This DOT

45 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult lymphoma	DISK8IZR	Definitive	Biomarker	[1]
Familial prostate carcinoma	DISL9KNO	Definitive	Genetic Variation	[2]
Fanconi anemia complementation group N	DIS0WTZ6	Definitive	Autosomal recessive	[3]
Gastric adenocarcinoma	DISWWLTC	Definitive	Biomarker	[4]
Hereditary breast carcinoma	DISAEZT5	Definitive	Autosomal dominant	[3]
Invasive breast carcinoma	DISANYTW	Definitive	Genetic Variation	[5]
Lymphoma	DISN6V4S	Definitive	Biomarker	[1]
Matthew-Wood syndrome	DISA7HR7	Definitive	Genetic Variation	[6]
Pediatric lymphoma	DIS51BK2	Definitive	Biomarker	[1]
Pure red-cell aplasia	DIST91OT	Definitive	Biomarker	[2]
Stomach cancer	DISKIJSX	Definitive	Genetic Variation	[7]
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[8]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[8]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[9]
Beckwith-Wiedemann syndrome	DISH15GR	Strong	Genetic Variation	[10]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[11]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[12]
Head and neck cancer	DISBPSQZ	Strong	Biomarker	[13]
Head and neck carcinoma	DISOU1DS	Strong	Biomarker	[13]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Genetic Variation	[14]
Lynch syndrome	DIS3IW5F	Strong	Genetic Variation	[15]
Malignant neoplasm	DISS6SNG	Strong	Genetic Variation	[16]
Metastatic prostate carcinoma	DISVBEZ9	Strong	Genetic Variation	[15]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[9]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Genetic Variation	[6]
Pancreatic cancer, susceptibility to, 3	DISFLIBD	Strong	Autosomal dominant	[17]
Pancreatic ductal carcinoma	DIS26F9Q	Strong	Biomarker	[18]
Pancytopenia	DISVKEHV	Strong	Biomarker	[19]
Familial adenomatous polyposis	DISW53RE	moderate	Genetic Variation	[20]
Familial ovarian cancer	DISGLR2C	Moderate	Autosomal dominant	[3]
Neuroendocrine neoplasm	DISNPLOO	moderate	Genetic Variation	[21]
Pancreatic tumour	DIS3U0LK	moderate	Biomarker	[22]
Triple negative breast cancer	DISAMG6N	moderate	Genetic Variation	[12]
Fanconi's anemia	DISGW6Q8	Supportive	Autosomal recessive	[23]
Gastric cancer	DISXGOUK	Disputed	Genetic Variation	[7]
Hereditary neoplastic syndrome	DISGXLG5	Disputed	CausalMutation	[24]
Breast disorder	DISJTGMA	Limited	Genetic Variation	[25]
Fanconi anemia complementation group A	DIS8PZLI	Limited	Biomarker	[26]
Hereditary nonpolyposis colon cancer	DISPA49R	Limited	Autosomal dominant	[3]
Lynch syndrome 1	DISSABLZ	Limited	Biomarker	[27]
Lynch syndrome 2	DISRLYU1	Limited	Biomarker	[27]
Prostate cancer	DISF190Y	Limited	Genetic Variation	[28]
Prostate carcinoma	DISMJPLE	Limited	Genetic Variation	[28]
Prostate neoplasm	DISHDKGQ	Limited	Biomarker	[29]

14 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Partner and localizer of BRCA2 (PALB2).	[30]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Partner and localizer of BRCA2 (PALB2).	[31]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Partner and localizer of BRCA2 (PALB2).	[32]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Partner and localizer of BRCA2 (PALB2).	[33]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Partner and localizer of BRCA2 (PALB2).	[34]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Partner and localizer of BRCA2 (PALB2).	[35]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Partner and localizer of BRCA2 (PALB2).	[36]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Partner and localizer of BRCA2 (PALB2).	[36]
Mitomycin	DMH0ZJE	Approved	Mitomycin decreases the expression of Partner and localizer of BRCA2 (PALB2).	[36]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of Partner and localizer of BRCA2 (PALB2).	[36]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of Partner and localizer of BRCA2 (PALB2).	[36]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Partner and localizer of BRCA2 (PALB2).	[37]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Partner and localizer of BRCA2 (PALB2).	[39]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Partner and localizer of BRCA2 (PALB2).	[42]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Partner and localizer of BRCA2 (PALB2).	[38]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Partner and localizer of BRCA2 (PALB2).	[40]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Partner and localizer of BRCA2 (PALB2).	[41]

References

• [1] Defects of FA/BRCA pathway in lymphoma cell lines.Int J Hematol. 2008 Dec;88(5):543-550. doi: 10.1007/s12185-008-0199-8. Epub 2008 Nov 15.
• [2] Analysis of the gene coding for the BRCA2-interacting protein PALB2 in hereditary prostate cancer.Prostate. 2008 May 1;68(6):675-8. doi: 10.1002/pros.20729.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] Pathogenic Germline Variants in 10,389 Adult Cancers.Cell. 2018 Apr 5;173(2):355-370.e14. doi: 10.1016/j.cell.2018.03.039.
• [5] Is RNASEL:p.Glu265* a modifier of early-onset breast cancer risk for carriers of high-risk mutations?.BMC Cancer. 2018 Feb 8;18(1):165. doi: 10.1186/s12885-018-4028-z.
• [6] Phase II trial of veliparib in patients with previously treated BRCA-mutated pancreas ductal adenocarcinoma.Eur J Cancer. 2018 Jan;89:19-26. doi: 10.1016/j.ejca.2017.11.004. Epub 2017 Dec 8.
• [7] PALB2 c.2257C>T truncating variant is a Greek founder and is associated with high breast cancer risk.J Hum Genet. 2019 Aug;64(8):767-773. doi: 10.1038/s10038-019-0612-6. Epub 2019 May 14.
• [8] Germline Genetic Predisposition to Hematologic Malignancy.J Clin Oncol. 2017 Mar 20;35(9):1018-1028. doi: 10.1200/JCO.2016.70.8644. Epub 2017 Feb 13.
• [9] Association of PALB2 Messenger RNA Expression with Platinum-Docetaxel Efficacy in Advanced Non-Small Cell Lung Cancer.J Thorac Oncol. 2019 Feb;14(2):304-310. doi: 10.1016/j.jtho.2018.10.168. Epub 2018 Nov 22.
• [10] Genomic profiles of a hepatoblastoma from a patient with Beckwith-Wiedemann syndrome with uniparental disomy on chromosome 11p15 and germline mutation of APC and PALB2.Oncotarget. 2017 Aug 24;8(54):91950-91957. doi: 10.18632/oncotarget.20515. eCollection 2017 Nov 3.
• [11] Propensity score-based nonparametric test revealing genetic variants underlying bipolar disorder.Genet Epidemiol. 2011 Feb;35(2):125-32. doi: 10.1002/gepi.20558.
• [12] Spectrum and clinical relevance of PALB2 germline mutations in 7657 Chinese BRCA1/2-negative breast cancer patients.Breast Cancer Res Treat. 2020 Feb;179(3):605-614. doi: 10.1007/s10549-019-05483-7. Epub 2019 Nov 25.
• [13] Assessment of DNA repair susceptibility genes identified by whole exome sequencing in head and neck cancer.DNA Repair (Amst). 2018 Jun-Jul;66-67:50-63. doi: 10.1016/j.dnarep.2018.04.005. Epub 2018 Apr 26.
• [14] Germline pathogenic variants in PALB2 and other cancer-predisposing genes in families with hereditary diffuse gastric cancer without CDH1 mutation: a whole-exome sequencing study.Lancet Gastroenterol Hepatol. 2018 Jul;3(7):489-498. doi: 10.1016/S2468-1253(18)30079-7. Epub 2018 Apr 27.
• [15] Metastatic Prostate Cancer: Effects of Genetic Testing on Care.Clin J Oncol Nurs. 2019 Feb 1;23(1):32-35. doi: 10.1188/19.CJON.32-35.
• [16] Exploring the roles of PALB2 at the crossroads of DNA repair and cancer.Biochem J. 2014 Jun 15;460(3):331-42. doi: 10.1042/BJ20140208.
• [17] Current Approaches to Pancreatic Cancer Screening. Am J Pathol. 2019 Jan;189(1):22-35. doi: 10.1016/j.ajpath.2018.09.013.
• [18] Mutations in BRCA1, BRCA2, and PALB2, and a panel of 50 cancer-associated genes in pancreatic ductal adenocarcinoma.Sci Rep. 2018 May 25;8(1):8105. doi: 10.1038/s41598-018-26526-x.
• [19] Individuals with FANCM biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility.Genet Med. 2018 Apr;20(4):452-457. doi: 10.1038/gim.2017.123. Epub 2017 Aug 24.
• [20] Familial pancreatic cancer--current knowledge.Nat Rev Gastroenterol Hepatol. 2012 Aug;9(8):445-53. doi: 10.1038/nrgastro.2012.111. Epub 2012 Jun 5.
• [21] Emerging frontiers in pancreatic cancer research: elaboration of key genes, cells and the extracellular milieu.Curr Opin Gastroenterol. 2012 Sep;28(5):516-22. doi: 10.1097/MOG.0b013e3283567f69.
• [22] Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer.Nat Genet. 2015 Aug;47(8):911-6. doi: 10.1038/ng.3341. Epub 2015 Jun 22.
• [23] Fanconi Anemia. 2002 Feb 14 [updated 2021 Jun 3]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [24] A high frequency of PALB2 mutations in Jamaican patients with breast cancer.Breast Cancer Res Treat. 2017 Apr;162(3):591-596. doi: 10.1007/s10549-017-4148-1. Epub 2017 Feb 13.
• [25] The prevalence of PALB2 germline mutations in BRCA1/BRCA2 negative Chinese women with early onset breast cancer or affected relatives.Breast Cancer Res Treat. 2009 Apr;114(3):457-62. doi: 10.1007/s10549-008-0036-z. Epub 2008 Apr 30.
• [26] Novel RNA and DNA strand exchange activity of the PALB2 DNA binding domain and its critical role for DNA repair in cells.Elife. 2019 Apr 29;8:e44063. doi: 10.7554/eLife.44063.
• [27] Inherited DNA-Repair Defects in Colorectal Cancer.Am J Hum Genet. 2018 Mar 1;102(3):401-414. doi: 10.1016/j.ajhg.2018.01.018. Epub 2018 Feb 22.
• [28] Bringing Prostate Cancer Germline Genetics into Clinical Practice.J Urol. 2019 Aug;202(2):223-230. doi: 10.1097/JU.0000000000000137. Epub 2019 Jul 8.
• [29] The long tail of oncogenic drivers in prostate cancer.Nat Genet. 2018 May;50(5):645-651. doi: 10.1038/s41588-018-0078-z. Epub 2018 Apr 2.
• [30] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [31] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [32] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [33] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [34] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [35] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [36] Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology. 2014 Jan 6;315:8-16. doi: 10.1016/j.tox.2013.10.009. Epub 2013 Nov 6.
• [37] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [38] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [39] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [40] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [41] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [42] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.