Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLK1420)

• DOT Name: Dynein regulatory complex subunit 2 (CCDC65)
• Synonyms: Coiled-coil domain-containing protein 65; Testis development protein NYD-SP28
• Gene Name: CCDC65
• Related Disease:
  Primary ciliary dyskinesia 1
  Primary ciliary dyskinesia 27
  Primary ciliary dyskinesia
• UniProt ID: DRC2_HUMAN
• PDB ID: 8J07
• Pfam ID: PF14772
• Sequence:
  MPKKEKMAKTPLSDEKQLLLFQQKLLAEEEMAKKKERLLSQFLKDKLAKEEHNSALNLNK
  INTQWRTVLREVKTRELHKDIEILSQTFERVVDCKDNVIKSLAKDLSEAEEQYAHALRSH
  LHNVDQLLALQRHRLSLLEESYNMELEALTKEFETERKTIIDQHEKEIHYLQDIFMAMEQ
  NYIDSEYESKLEFQSMWNDLKNMNLEEKHFLRLHLENRVEDLWRKFQDVLKNYTDATEDR
  KAAFETLQVKDEKSSKEIEVQMKKIQKLQDAITISKGKIMIHSRESEDENRYIRNDKELV
  LVQLRKLKAQRTQARAASQKNLVRLTLESNATLKALRKIVDKGEKILKLAEICRKFETEE
  EKVLPFYSSVLTPKEQEGIQKNNLEELTEELTKVMVDYIGMENFWKRYNKVKLEQLSLQH
  RRAQLLDINGKLREMLKQYLDGISVSDEVLSQLNPLFIVNYQSNLLQPLSIRIAHPGDKQ
  HPTT
• Function: Component of the nexin-dynein regulatory complex (N-DRC), a key regulator of ciliary/flagellar motility which maintains the alignment and integrity of the distal axoneme and regulates microtubule sliding in motile axonemes. Plays a critical role in the assembly of N-DRC and also stabilizes the assembly of multiple inner dynein arms and radial spokes. Coassembles with DRC1 to form a central scaffold needed for assembly of the N-DRC and its attachment to the outer doublet microtubules.
• Tissue Specificity: Highly expressed in adult testis, in spermatocytes and spermatids. Also observed in spermatogonia. Not detected in Leydig cells, nor in fetal testis (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Primary ciliary dyskinesia 1	DISPGX6H	Strong	GermlineCausalMutation	[1]
Primary ciliary dyskinesia 27	DIS23D7P	Strong	Autosomal recessive	[2]
Primary ciliary dyskinesia	DISOBC7V	Supportive	Autosomal dominant	[1]

2 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 Dynein regulatory complex subunit 2 (CCDC65).	[3]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Dynein regulatory complex subunit 2 (CCDC65).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Dynein regulatory complex subunit 2 (CCDC65).	[4]

References

• [1] Zebrafish Ciliopathy Screen Plus Human Mutational Analysis Identifies C21orf59 and CCDC65 Defects as Causing Primary Ciliary Dyskinesia. Am J Hum Genet. 2013 Oct 3;93(4):672-86. doi: 10.1016/j.ajhg.2013.08.015.
• [2] CCDC65 mutation causes primary ciliary dyskinesia with normal ultrastructure and hyperkinetic cilia. PLoS One. 2013 Aug 26;8(8):e72299. doi: 10.1371/journal.pone.0072299. eCollection 2013.
• [3] 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.
• [4] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [5] 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.