KDM2B is broadly and highly expressed in embryonic tissues (especially in the developing central nervous system of vertebrates). Expression of KDM2B is also retained in most organs in adults.[2] The protein is present in the nucleoplasm and is enriched in the nucleolus where it binds the transcribed region of ribosomal RNA to represses the transcription of ribosomal RNA genes which inhibits cell growth and proliferation.[3]
Structure
KDM2B protein has several domains including a JmjC domain that has a histone demethylase activity demethylating trimethylated Lys-4 and dimethylated Lys-36 of histone H3.[4][3] It is also the core scaffold of the non-canonical polycomb repressive complex 1.1 (ncPRC1.1) containing BCOR, PCGF1, RING1/2 and RYBP that mono-ubiquitylates histone H2A on K119.[5][6][7][8]
Function
This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class. Multiple alternatively splicedtranscript variants have been found for this gene, but the full-length nature of some variants has not been determined.[1]
As part of the ncPRC1.1 complex, KDM2B was found to rapidly and transiently recruite to sites of DNA damage in a PARP1- and TIMELESS-dependent manner to promote mono-ubiquitylation of histone H2A on K119 with concomitant local decrease of H2A levels and an increase of H2A.Z. These events promote transcriptional repression at DNA lesions, double strand break signaling, and homologous recombination repair. The activity of the ncPRC1.1 complex at DNA lesions was necessary for the proper recruitment of the two canonical PRC1 complexes (cPRC1.2 and cPRC1.4), defined by their PCGF subunits, MEL18 and BMI1 respectively. Therefore, recruitment of the ncPRC1.1 complex represents an early and critical regulatory step in homologous recombination repair.[9]
Clinical significance
Loss of KDM2B leads to severe developmental defects (growth defects in the brain, including failure of neural tube closure and craniofacial malformations, hematopoietic development) leading to embryonic lethality[10]
↑Wang H, Wang L, Erdjument-Bromage H, Vidal M, Tempst P, Jones RS, Zhang Y (October 2004). "Role of histone H2A ubiquitination in Polycomb silencing". Nature. 431 (7010): 873–8. doi:10.1038/nature02985. PMID15386022.
Further reading
Fujino T, Hasegawa M, Shibata S, Kishimoto T, Imai S, Takano T (May 2000). "PCCX1, a novel DNA-binding protein with PHD finger and CXXC domain, is regulated by proteolysis". Biochemical and Biophysical Research Communications. 271 (2): 305–10. doi:10.1006/bbrc.2000.2614. PMID10799292.
Frescas D, Guardavaccaro D, Bassermann F, Koyama-Nasu R, Pagano M (November 2007). "JHDM1B/FBXL10 is a nucleolar protein that represses transcription of ribosomal RNA genes". Nature. 450 (7167): 309–13. doi:10.1038/nature06255. PMID17994099.
Koyama-Nasu R, David G, Tanese N (September 2007). "The F-box protein Fbl10 is a novel transcriptional repressor of c-Jun". Nature Cell Biology. 9 (9): 1074–80. doi:10.1038/ncb1628. PMID17704768.
