Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVRDL6U)

• DOT Name: Abasic site processing protein HMCES (HMCES)
• Synonyms: EC 4.-.-.-; Embryonic stem cell-specific 5-hydroxymethylcytosine-binding protein; ES cell-specific 5hmC-binding protein; Peptidase HMCES; EC 3.4.-.-; SRAP domain-containing protein 1
• Gene Name: HMCES
• Related Disease:
  Norrie disease
  Multiple sclerosis
• UniProt ID: HMCES_HUMAN
• PDB ID: 5KO9; 6OE7; 6OEA; 6OEB; 6OOV
• EC Number: 3.4.-.-; 4.-.-.-
• Pfam ID: PF02586
• Sequence:
  MCGRTSCHLPRDVLTRACAYQDRRGQQRLPEWRDPDKYCPSYNKSPQSNSPVLLSRLHFE
  KDADSSERIIAPMRWGLVPSWFKESDPSKLQFNTTNCRSDTVMEKRSFKVPLGKGRRCVV
  LADGFYEWQRCQGTNQRQPYFIYFPQIKTEKSGSIGAADSPENWEKVWDNWRLLTMAGIF
  DCWEPPEGGDVLYSYTIITVDSCKGLSDIHHRMPAILDGEEAVSKWLDFGEVSTQEALKL
  IHPTENITFHAVSSVVNNSRNNTPECLAPVDLVVKKELRASGSSQRMLQWLATKSPKKED
  SKTPQKEESDVPQWSSQFLQKSPLPTKRGTAGLLEQWLKREKEEEPVAKRPYSQ
• Function: Sensor of abasic sites in single-stranded DNA (ssDNA) required to preserve genome integrity by promoting error-free repair of abasic sites. Acts as an enzyme that recognizes and binds abasic sites in ssDNA at replication forks and chemically modifies the lesion by forming a covalent cross-link with DNA: forms a stable thiazolidine linkage between a ring-opened abasic site and the alpha-amino and sulfhydryl substituents of its N-terminal catalytic cysteine residue. Promotes error-free repair by protecting abasic sites from translesion synthesis (TLS) polymerases and endonucleases that are error-prone and would generate mutations and double-strand breaks. The HMCES DNA-protein cross-link is then either reversed or degraded. HMCES is able to catalyze the reversal of its thiazolidine cross-link and cycle between a cross-link and a non-cross-linked state depending on DNA context: mediates self-reversal of the thiazolidine cross-link in double stranded DNA, allowing APEX1 to initiate downstream repair of abasic sites. The HMCES DNA-protein cross-link can also be degraded by the SPRTN metalloprotease following unfolding by the BRIP1/FANCJ helicase. Has preference for ssDNA, but can also accommodate double-stranded DNA with 3' or 5' overhang (dsDNA), and dsDNA-ssDNA 3' junction. Plays a protective role during somatic hypermutation of immunoglobulin genes in B-cells: acts via its ability to form covalent cross-links with abasic sites, thereby limiting the accumulation of deletions in somatic hypermutation target regions. Also involved in class switch recombination (CSR) in B-cells independently of the formation of a DNA-protein cross-link: acts by binding and protecting ssDNA overhangs to promote DNA double-strand break repair through the microhomology-mediated alternative-end-joining (Alt-EJ) pathway. Acts as a protease: mediates autocatalytic processing of its N-terminal methionine in order to expose the catalytic cysteine.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Norrie disease	DISOCDDU	Strong	Biomarker	[1]
Multiple sclerosis	DISB2WZI	Limited	Biomarker	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Abasic site processing protein HMCES (HMCES) affects the response to substance of Fluorouracil.	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Abasic site processing protein HMCES (HMCES).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Abasic site processing protein HMCES (HMCES).	[4]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Abasic site processing protein HMCES (HMCES).	[5]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Abasic site processing protein HMCES (HMCES).	[5]
Bleomycin	DMNER5S	Approved	Bleomycin decreases the expression of Abasic site processing protein HMCES (HMCES).	[5]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Abasic site processing protein HMCES (HMCES).	[6]

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 increases the methylation of Abasic site processing protein HMCES (HMCES).	[7]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Abasic site processing protein HMCES (HMCES).	[8]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Abasic site processing protein HMCES (HMCES).	[9]

References

• [1] The Norrie disease gene maps to a 150 kb region on chromosome Xp11.3.Hum Mol Genet. 1992 May;1(2):83-9. doi: 10.1093/hmg/1.2.83.
• [2] Class II HLA-DC beta-chain DNA restriction fragments differentiate among HLA-DR2 individuals in insulin-dependent diabetes and multiple sclerosis.Proc Natl Acad Sci U S A. 1984 Mar;81(6):1774-8. doi: 10.1073/pnas.81.6.1774.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [5] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
• [6] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [7] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [8] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [9] 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.
• [10] Mechanistic and predictive profiling of 5-Fluorouracil resistance in human cancer cells. Cancer Res. 2004 Nov 15;64(22):8167-76. doi: 10.1158/0008-5472.CAN-04-0970.