Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ7M1OH)

• DOT Name: KH domain-containing protein 3 (KHDC3L)
• Synonyms: ES cell-associated transcript 1 protein; KHDC3-like protein
• Gene Name: KHDC3L
• Related Disease:
  Gestational trophoblastic neoplasia
  Hydatidiform mole, recurrent, 2
  Melanocytic nevus
  Complete hydatidiform mole
• UniProt ID: KHDC3_HUMAN
• Pfam ID: PF16005
• Sequence:
  MDAPRRFPTLVQLMQPKAMPVEVLGHLPKRFSWFHSEFLKNPKVVRLEVWLVEKIFGRGG
  ERIPHVQGMSQILIHVNRLDPNGEAEILVFGRPSYQEDTIKMIMNLADYHRQLQAKGSGK
  ALAQDVATQKAETQRSSIEVREAGTQRSVEVREAGTQRSVEVQEVGTQGSPVEVQEAGTQ
  QSLQAANKSGTQRSPEAASKAVTQRFREDARDPVTRL
• Function: As part of the OOEP-KHDC3 scaffold, recruits BLM and TRIM25 to DNA replication forks, thereby promoting the ubiquitination of BLM by TRIM25, enhancing BLM retainment at replication forks and therefore promoting stalled replication fork restart. Regulates homologous recombination-mediated DNA repair via recruitment of RAD51 to sites of DNA double-strand breaks, and sustainment of PARP1 activity, which in turn modulates downstream ATM or ATR activation. Activation of ATM or ATR in response to DNA double-strand breaks may be cell-type specific. Its role in DNA double-strand break repair is independent of its role in restarting stalled replication forks. As a member of the subcortical maternal complex (SCMC), plays an essential role for zygotes to progress beyond the first embryonic cell divisions via regulation of actin dynamics. Required for maintenance of euploidy during cleavage-stage embryogenesis. Required for the formation of F-actin cytoplasmic lattices in oocytes which in turn are responsible for symmetric division of zygotes via the regulation of mitotic spindle formation and positioning. Ensures proper spindle assembly by regulating the localization of AURKA via RHOA signaling and of PLK1 via a RHOA-independent process. Required for the localization of MAD2L1 to kinetochores to enable spindle assembly checkpoint function. Promotes neural stem cell neurogenesis and neuronal differentiation in the hippocampus. May regulate normal development of learning, memory and anxiety. Capable of binding RNA.
• Tissue Specificity: Expression appears to be maximal in germinal vesicle oocytes, it tails off through metaphase II oocytes and is undetectable following the completion of the oocyte to embryo transition.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gestational trophoblastic neoplasia	DIS4EJNA	Strong	Genetic Variation	[1]
Hydatidiform mole, recurrent, 2	DISD8XU3	Strong	Autosomal recessive	[2]
Melanocytic nevus	DISYS32D	Strong	Genetic Variation	[3]
Complete hydatidiform mole	DIS5QPI0	Supportive	Autosomal recessive	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of KH domain-containing protein 3 (KHDC3L).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of KH domain-containing protein 3 (KHDC3L).	[6]

References

• [1] Hepatic toxicity following actinomycin D chemotherapy in treatment of familial gestational trophoblastic neoplasia: A case report.Medicine (Baltimore). 2018 Sep;97(38):e12424. doi: 10.1097/MD.0000000000012424.
• [2] Identification of 13 novel NLRP7 mutations in 20 families with recurrent hydatidiform mole; missense mutations cluster in the leucine-rich region. J Med Genet. 2009 Aug;46(8):569-75. doi: 10.1136/jmg.2008.064196. Epub 2009 Feb 25.
• [3] NLRP7 and KHDC3L variants in Chinese patients with recurrent hydatidiform moles.Jpn J Clin Oncol. 2019 Jul 1;49(7):620-627. doi: 10.1093/jjco/hyz036.
• [4] Mutations causing familial biparental hydatidiform mole implicate c6orf221 as a possible regulator of genomic imprinting in the human oocyte. Am J Hum Genet. 2011 Sep 9;89(3):451-8. doi: 10.1016/j.ajhg.2011.08.002. Epub 2011 Sep 1.
• [5] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [6] 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.