Biology:DDB2

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A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

DNA damage-binding protein 2 is a protein that in humans is encoded by the DDB2 gene.[1][2]

Structure

As indicated by Rapić-Otrin et al. in 2003,[3] the DDB2 gene is located on human chromosome 11p11.2, spans a region of approximately 24 – 26 kb and includes 10 exons. The DDB2 protein contains five putative WD40 repeats (sequences of about 40 amino acids that can interact with each other) positioned downstream from the second exon. The WD40 motif identified in DDB2 is characteristic of proteins involved in the recognition of chromatin proteins. The C-terminal region of DDB2 (a 48 kDa molecular weight protein) is essential for binding to DDB1 (a larger 127 kDa protein). Together, the two proteins form a UV-damaged DNA binding protein complex (UV-DDB).[4]

Deficiency in humans

If humans have a mutation in each copy of their DDB2 gene, this causes a mild form of the human disease xeroderma pigmentosum, called XPE.[3] Patients in the XPE group have mild dermatological manifestations and are neurologically unaffected. Mutation in the DDB2 gene causes a deficiency in nucleotide excision repair of DNA. This deficiency is also mild, showing 40 to 60% of normal repair capability and a modest sensitivity to UV light in comparison to the sensitivities of cells defective in the other XP genes XPA, XPB, XPC, XPD, XPF and XPG.[5]

Function

Binding to damaged DNA

As shown by Wittschieben et al.,[6] when DDB2 is in a complex with DDB1, forming the heterodimer DDB, this complex binds strongly to DNA containing one type of UV light-induced photoproduct [the (6-4) photoproduct], to DNA with an abasic site, to DNA containing mismatches without a covalent lesion, and to “compound” lesions containing both mismatches and lesions. The heterodimer DDB binds with intermediate strength to DNA containing another UV light-induced photoproduct (the cyclobutane pyrimidine dimer), and binds weakly to DNA that has no DNA damage. The DDB2 component of the heterodimer contains the specificity for binding to damaged DNA, since a heterodimer DDB complex containing amino acid substitutions in the DDB2 subunit, as found in XP-E patients, is very deficient in binding to damaged DNA. DDB1 and DDB2, each acting alone, do not bind DNA.

Chromatin remodeling

The packaging of eukaryotic DNA into chromatin presents a barrier to all DNA-based processes that require recruitment of enzymes to their sites of action. To allow the critical cellular process of DNA repair, the chromatin must be relaxed.

DDB2, in its heterodimeric complex with DDB1, and further complexed with the ubiquitin ligase protein CUL4A[7] and with PARP1[8] rapidly associates with UV-induced damage within chromatin, with half-maximum association completed in 40 seconds.[7] The PARP1 protein, attached to both DDB1 and DDB2, then PARylates (creates a poly-ADP ribose chain) on DDB2 that attracts the DNA remodeling protein ALC1.[8] Action of ALC1 relaxes the chromatin at the site of UV damage to DNA. This relaxation allows other proteins in the nucleotide excision repair pathway to enter the chromatin and repair the DNA damaged by the UV-induced presence of cyclobutane pyrimidine dimers.

Other functions

In 2015, Zhu et al.[9] showed that DDB2 down-regulates the acetylation of lysine 56 in histone H3 (H3K56Ac) after UV-induced DNA damage through DDB2 interaction with histone deacetylases 1 and 2. Decreased acetylation of histones decreases transcription of associated genes in the DNA wrapped around the histones.

In 2016, Zou et al.[10] showed that DDB2 is involved in cell cycle arrest and homologous recombinational DNA repair after cells are subjected to ionizing radiation.

In 2016, Christmann et al.[11] showed that exposure of cells to the carcinogenic benzo(a)pyrene metabolite BPDE caused prompt and sustained upregulation of DDB2. This contributed to enhanced removal of BPDE adducts from DNA.

In 2017, Fantini et al.[12] showed that DDB2, in association with XRCC5 and XRCC6 (otherwise known as Ku80 and Ku70, which make up the Ku heterodimer), has transcriptional activities. The DDB2/Ku effects on transcription are separate from the actions of the Ku heterodimer in non-homologous end joining DNA repair.

References

  1. ↑ "Characterization of a human DNA damage binding protein implicated in xeroderma pigmentosum E". The Journal of Biological Chemistry 268 (28): 21293–300. October 1993. doi:10.1016/S0021-9258(19)36923-6. PMID 8407967. 
  2. ↑ "Chromosomal localization and cDNA cloning of the genes (DDB1 and DDB2) for the p127 and p48 subunits of a human damage-specific DNA binding protein". Genomics 29 (1): 62–9. September 1995. doi:10.1006/geno.1995.1215. PMID 8530102. 
  3. ↑ 3.0 3.1 "True XP group E patients have a defective UV-damaged DNA binding protein complex and mutations in DDB2 which reveal the functional domains of its p48 product". Human Molecular Genetics 12 (13): 1507–22. July 2003. doi:10.1093/hmg/ddg174. PMID 12812979. 
  4. ↑ "Sequential binding of UV DNA damage binding factor and degradation of the p48 subunit as early events after UV irradiation". Nucleic Acids Research 30 (11): 2588–98. June 2002. doi:10.1093/nar/30.11.2588. PMID 12034848. 
  5. ↑ "Relationship of the xeroderma pigmentosum group E DNA repair defect to the chromatin and DNA binding proteins UV-DDB and replication protein A". Molecular and Cellular Biology 18 (6): 3182–90. June 1998. doi:10.1128/mcb.18.6.3182. PMID 9584159. 
  6. ↑ "DDB1-DDB2 (xeroderma pigmentosum group E) protein complex recognizes a cyclobutane pyrimidine dimer, mismatches, apurinic/apyrimidinic sites, and compound lesions in DNA". The Journal of Biological Chemistry 280 (48): 39982–9. December 2005. doi:10.1074/jbc.M507854200. PMID 16223728. 
  7. ↑ 7.0 7.1 "Dynamic in vivo interaction of DDB2 E3 ubiquitin ligase with UV-damaged DNA is independent of damage-recognition protein XPC". Journal of Cell Science 120 (Pt 15): 2706–16. August 2007. doi:10.1242/jcs.008367. PMID 17635991. 
  8. ↑ 8.0 8.1 "PARP1 promotes nucleotide excision repair through DDB2 stabilization and recruitment of ALC1". The Journal of Cell Biology 199 (2): 235–49. October 2012. doi:10.1083/jcb.201112132. PMID 23045548. 
  9. ↑ "Damaged DNA-binding protein down-regulates epigenetic mark H3K56Ac through histone deacetylase 1 and 2". Mutation Research 776: 16–23. June 2015. doi:10.1016/j.mrfmmm.2015.01.005. PMID 26255936. 
  10. ↑ "DDB2 increases radioresistance of NSCLC cells by enhancing DNA damage responses". Tumour Biology 37 (10): 14183–14191. October 2016. doi:10.1007/s13277-016-5203-y. PMID 27553023. 
  11. ↑ "Adaptive upregulation of DNA repair genes following benzo(a)pyrene diol epoxide protects against cell death at the expense of mutations". Nucleic Acids Research 44 (22): 10727–10743. December 2016. doi:10.1093/nar/gkw873. PMID 27694624. 
  12. ↑ "Chromatin association of XRCC5/6 in the absence of DNA damage depends on the XPE gene product DDB2". Molecular Biology of the Cell 28 (1): 192–200. January 2017. doi:10.1091/mbc.E16-08-0573. PMID 28035050. 

Further reading

External links




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