XPC (gene)

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XPC
Protein XPC PDB 2A4J.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases XPC, RAD4, XP3, XPCC, p125, xeroderma pigmentosum, complementation group C, XPC complex subunit, DNA damage recognition and repair factor
External IDs MGI: 103557 HomoloGene: 3401 GeneCards: XPC
RNA expression pattern
PBB GE XPC 209375 at fs.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001145769
NM_004628

NM_009531

RefSeq (protein)

NP_004619

NP_033557.2
NP_033557

Location (UCSC) Chr 3: 14.15 – 14.18 Mb Chr 6: 91.49 – 91.52 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

Xeroderma pigmentosum, complementation group C, also known as XPC, is a protein which in humans is encoded by the XPC gene. XPC is involved in the recognition of bulky DNA adducts in nucleotide excision repair.[3] It is located on chromosome 3.[4]

Function[edit]

This gene encodes a component of the nucleotide excision repair (NER) pathway. There are multiple components involved in the NER pathway, including Xeroderma pigmentosum (XP) A-G and V, Cockayne syndrome (CS) A and B, and trichothiodystrophy (TTD) group A, etc. This component, XPC, plays an important role in the early steps of global genome NER, especially in damage recognition, open complex formation, and repair protein complex formation.[3]

The complex of XPC-RAD23B is the initial damage recognition factor in global genomic nucleotide excision repair (GG-NER).[5] XPC-RAD23B recognizes a wide variety of lesions that thermodynamically destabilize DNA duplexes, including UV-induced photoproducts (cyclopyrimidine dimers and 6-4 photoproducts ), adducts formed by environmental mutagens such as benzo[a]pyrene or various aromatic amines, certain oxidative endogenous lesions such as cyclopurines and adducts formed by cancer chemotherapeutic drugs such as cisplatin. The presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo.[6] Although most studies have been performed with XPC-RAD23B, it is part of a trimeric complex with centrin-2, a calcium-binding protein of the calmodulin family.[6]

Clinical significance[edit]

Mutations in this gene or some other NER components result in Xeroderma pigmentosum, a rare autosomal recessive disorder characterized by increased sensitivity to sunlight with the development of carcinomas at an early age.[3]

Cancer[edit]

DNA damage appears to be the primary underlying cause of cancer,[7][8] and deficiencies in DNA repair genes likely underlie many forms of cancer.[9][10] If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage may increase mutations due to error-prone translesion synthesis. Excess DNA damage may also increase epigenetic alterations due to errors during DNA repair.[11][12] Such mutations and epigenetic alterations may give rise to cancer.

Reductions in expression of DNA repair genes (usually caused by epigenetic alterations such as promoter hypermethylation) are very common in cancers, and are ordinarily much more frequent than mutational defects in DNA repair genes in cancers.[13] The table below shows that XPC expression was frequently epigenetically reduced in bladder cancer and also in non-small cell lung cancer, and also shows that XPC was more frequently reduced in the more advanced stages of these cancers.

Frequency of reduced expression of XPC in cancers, with stages of cancers indicated separately
Cancer Frequency Ref.
Bladder cancer 50% [14]
Papillary urothelial neoplasm of low malignant potential 35% [14]
Low grade papillary bladder cancer 42% [14]
High grade papillary bladder cancer 65% [14]
Non-small cell lung cancer (NSCLC) 70% [15]
NSCLC Stage I 62% [15]
NSCLC Stages II-III 77% [15]

While epigenetic hypermethylation of the promoter region of the XPC gene was shown to be associated with low expression of XPC,[14] another mode of epigenetic repression of XPC may also occur by over-expression of the microRNA miR-890.[16]

Interactions[edit]

XPC (gene) has been shown to interact with ABCA1,[17] CETN2[18] and XPB.[19]

References[edit]

  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ a b c "Entrez Gene: XPC xeroderma pigmentosum, complementation group C". 
  4. ^ http://www.omim.org/entry/278720. Retrieved 12 December 2014.  Missing or empty |title= (help)
  5. ^ Sugasawa K, Ng JM, Masutani C, Iwai S, van der Spek PJ, Eker AP, Hanaoka F, Bootsma D, Hoeijmakers JH (1998). "Xeroderma pigmentosum group C protein complex is the initiator of global genome nucleotide excision repair". Mol. Cell. 2 (2): 223–32. doi:10.1016/s1097-2765(00)80132-x. PMID 9734359. 
  6. ^ a b Schärer OD (Oct 2013). "Nucleotide excision repair in eukaryotes". Cold Spring Harbor Perspectives in Biology. 5 (10): a012609. doi:10.1101/cshperspect.a012609. PMC 3783044Freely accessible. PMID 24086042. 
  7. ^ Kastan MB (2008). "DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture". Mol. Cancer Res. 6 (4): 517–24. doi:10.1158/1541-7786.MCR-08-0020. PMID 18403632. 
  8. ^ Bernstein C, Prasad AR, Nfonsam V, Bernstein H. (2013). DNA Damage, DNA Repair and Cancer, New Research Directions in DNA Repair, Prof. Clark Chen (Ed.), ISBN 978-953-51-1114-6, InTech, http://www.intechopen.com/books/new-research-directions-in-dna-repair/dna-damage-dna-repair-and-cancer
  9. ^ Harper JW, Elledge SJ (2007). "The DNA damage response: ten years after". Mol. Cell. 28 (5): 739–45. doi:10.1016/j.molcel.2007.11.015. PMID 18082599. 
  10. ^ Dietlein F, Reinhardt HC (2014). "Molecular pathways: exploiting tumor-specific molecular defects in DNA repair pathways for precision cancer therapy". Clin. Cancer Res. 20 (23): 5882–7. doi:10.1158/1078-0432.CCR-14-1165. PMID 25451105. 
  11. ^ O'Hagan HM, Mohammad HP, Baylin SB (2008). "Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island". PLoS Genetics. 4 (8): e1000155. doi:10.1371/journal.pgen.1000155. PMC 2491723Freely accessible. PMID 18704159. 
  12. ^ Cuozzo C, Porcellini A, Angrisano T, Morano A, Lee B, Di Pardo A, Messina S, Iuliano R, Fusco A, Santillo MR, Muller MT, Chiariotti L, Gottesman ME, Avvedimento EV (Jul 2007). "DNA damage, homology-directed repair, and DNA methylation". PLoS Genetics. 3 (7): e110. doi:10.1371/journal.pgen.0030110. PMC 1913100Freely accessible. PMID 17616978. 
  13. ^ Carol Bernstein and Harris Bernstein (2015). Epigenetic Reduction of DNA Repair in Progression to Cancer, Advances in DNA Repair, Prof. Clark Chen (Ed.), ISBN 978-953-51-2209-8, InTech, Available from: http://www.intechopen.com/books/advances-in-dna-repair/epigenetic-reduction-of-dna-repair-in-progression-to-cancer
  14. ^ a b c d e Yang J, Xu Z, Li J, Zhang R, Zhang G, Ji H, Song B, Chen Z (2010). "XPC epigenetic silence coupled with p53 alteration has a significant impact on bladder cancer outcome". J. Urol. 184 (1): 336–43. doi:10.1016/j.juro.2010.03.044. PMID 20488473. 
  15. ^ a b c Yeh KT, Wu YH, Lee MC, Wang L, Li CT, Chen CY, Lee H (2012). "XPC mRNA level may predict relapse in never-smokers with non-small cell lung cancers". Ann. Surg. Oncol. 19 (3): 734–42. doi:10.1245/s10434-011-1992-9. PMID 21861227. 
  16. ^ Hatano K, Kumar B, Zhang Y, Coulter JB, Hedayati M, Mears B, Ni X, Kudrolli TA, Chowdhury WH, Rodriguez R, DeWeese TL, Lupold SE (2015). "A functional screen identifies miRNAs that inhibit DNA repair and sensitize prostate cancer cells to ionizing radiation". Nucleic Acids Res. 43 (8): 4075–86. doi:10.1093/nar/gkv273. PMC 4417178Freely accessible. PMID 25845598. 
  17. ^ Shimizu Y, Iwai S, Hanaoka F, Sugasawa K (January 2003). "Xeroderma pigmentosum group C protein interacts physically and functionally with thymine DNA glycosylase". EMBO J. 22 (1): 164–73. doi:10.1093/emboj/cdg016. PMC 140069Freely accessible. PMID 12505994. 
  18. ^ Araki M, Masutani C, Takemura M, Uchida A, Sugasawa K, Kondoh J, Ohkuma Y, Hanaoka F (June 2001). "Centrosome protein centrin 2/caltractin 1 is part of the xeroderma pigmentosum group C complex that initiates global genome nucleotide excision repair". J. Biol. Chem. 276 (22): 18665–72. doi:10.1074/jbc.M100855200. PMID 11279143. 
  19. ^ Yokoi M, Masutani C, Maekawa T, Sugasawa K, Ohkuma Y, Hanaoka F (March 2000). "The xeroderma pigmentosum group C protein complex XPC-HR23B plays an important role in the recruitment of transcription factor IIH to damaged DNA". J. Biol. Chem. 275 (13): 9870–5. doi:10.1074/jbc.275.13.9870. PMID 10734143. 

Further reading[edit]

External links[edit]