Gene Family Responsible For Nucleotide Excision Repair Pathways Biology Essay

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Excision Repair Cross-Complementary gene family are responsible for Nucleotide Excision Repair pathways. This pathway undergoes a repairing process of the DNA that gets damaged by carcinogens of the mainstream smoke [i]. NER system is one of the basic mechanisms that a cell use in protection against genotoxic damage induced by UV-irradiation and exposure to chemical carcinogens. The process of repairing is basically in five steps:

Recognition of lesions by XPC-hHR23B complex.

Unwinding of helix at lesion site by DNA helicases, XPB and XPD.

Separating the damages and renewing the activity of XPA and RPA.

Incision of the damaged strand by XPG and XPF.

DNA gap synthesis by removal of 23mer-32mer oligonucleotide by DNA polymerase and later ligation by ligase I.

The NER process is divided into 2 pathways: global genome repair and transcription coupled repair. In TCR the lesion compose a block to DNA polymerase II initiating a signal for repair process. In GGR, deformed helix produced by bulky adducts recognized by XPC protein for repair process. [1]

1.1 ERCC2 gene

It is a protein that involves in transcription coupled nucleotide excision repair pathway. The gene encodes for 2.3 kb of mRNA having 22 exons and 21 introns. The protein is 760 amino acid polypeptide long and having a size of 87kDa. Any defect in this gene will lead to 3 different types of disorders like: xeroderma pigmentosum group D (XPD), trichothiodystropy (TTD) and cockayne syndrome.[2, 3, 4, 5].

1.2 Table

EC NO/Category

Chromosome Location

Sub cellular localization

Family

3.6.1.-

19q13.32

Intracellular

Helicase family & RAD3/XPD subfamily.

2. Structure

No structure is available till now.

3. Function

ERCC2 gene expresses XPD protein which is a part of the TFIIH basal transcription factor. The gene encodes the XPD DNA repair protein that has multiple regulatory cellular functions like nucleotide excision repair, basal transcription, cell cycle control, and apoptosis. [6] The main function of ERCC2 is nucleotide excision repair pathway by unlocking the strand near the damaged area. After the site is unlocked, transcription starts with help of DNA polymerase II supporting the CDK-activating kinase complex (CAK). This complex consists of CDK7, Cyclin H and MAT1 at the core of the TFIIH complex. They are ATP dependent and process starts from the 5'  3' end of the strand. [ii] The gene provides signal for the production of XPD protein. This protein plays a key role in the TFIIH complex which is responsible for two processes; gene transcription and damaged DNA repairing. This protein also helps to stabilise the TFIIH complex. The complex controls gene transcription and also regulates the activity of many different genes. There is another protein XPB produced from ERCC3 that works along with XPD to perform the gene transcription. [iii]

4. Pathway

Fig1. Above diagram shows nucleotide excision repair pathway of damaged DNA by radiation, oxygen radicals, hydrocarbons and chemicals used during chemotherapy.

DNA repair pathways are important for removal of lesions from the DNA strands for further transcription processes. There are 3 types of repair process; they are BER (Base Excision Repair), NER (Nucleotide Excision Repair) and MMR (Mismatch Repair). The gene, ERCC2 expresses XPD (Xeroderma Pigmentosum complementation Group D) protein, a component of the TFIIH complex which acts in the NER pathway of DNA repair. NER process undergoes damage recognition, local opening of the DNA duplex around the lesion, dual incision of the damaged DNA strand, gap repair synthesis and strand ligation. It has got 2 forms; GG-NER (Global Genomic-NER) and TC-NER (Transcription Coupled NER). Global Genomic NER are responsible for correcting damages in the DNA those are transcriptionally silent. The damages are recognised by XPC-hHR23D* (Xeroderma Pigmentosum Complementation Group-C), (Rad23 homolog B). Alternately in transcription coupled NER the transcription mechanism by DNA polymerase II gets stalled at the lesion site of the strand. Then polymerase II is replaced by CSA (Cockayne Syndrome A), CSB (Cockayne Syndrome B) and XAB2 (XPA Binding Protein 2). The above 2 process create a signal for the complex TFIIH for unwinding of the damaged strand. The GG-NER and TC-NER have the same identical process for the repair. TFIIH has 2 helicases, XPD and XPB that unwind the DNA duplex in the region of the lesion. Later incision is done by XPG (Xeroderma Pigmentosum complementation Group G) and ERCC1 (Excision Repair Cross Complementing Group 1) that cleaves at one strand of the DNA from 3'5' creating a 30 base oligonucleotide containing the lesion. Hence a gap is created in the stand which is later filled up by DNA Pol Delta or DNA Pol Epsilon. And finally sealed by DNA ligase I.

5. Mechanism

Web Refs:

http://cebp.aacrjournals.org/content/15/3/536.short

http://www.uniprot.org/uniprot/P18074#section_comments

http://ghr.nlm.nih.gov/gene/ERCC2

Article Refs:

Benhamou, S. and Sarasin, A. (2002). "ERCC2/XPD gene polymorphisms and cancer risk". Mutagenesis.17 (6), 463-469.

Coin, F., Marinoni, J. C., Rodolfo, C., Fribourg, S., Pedrini, A. M., Egly, J. M. (1998). "Mutations in the XPD helicase gene result in XP and TTD phenotypes, preventing interaction between XPD and the p44 subunit of TFIIH". Nat. Genet. 20(2), 184-188.

Vermeulen, W., Bergmann, E., Auriol, J., Rademakers, S., Frit, P., Appeldoorn, E., Hoeijmakers, J. H., Egly, J. M. (2000). "Sublimiting concentration of TFIIH transcription/DNA repair factor causes TTD-A trichothiodystrophy disorder". Nat. Genet. 26 (3), 307-313.

Iyer, N., Reagan, M. S., Wu, K. J., Canagarajah, B., Friedberg, E. C. (1996). "Interactions involving the human RNA polymerase II transcription/nucleotide excision repairs complex TFIIH, the nucleotide excision repair protein XPG, and Cockayne syndrome group B (CSB) protein". Biochemistry. 35 (7), 2157-2167.

Giglia-Mari, G., Coin, F., Ranish, J. A., Hoogstraten, D., Theil, A., Wijgers, N., Jaspers, N. G. J., Raams, A., Argentini, M., Spek, P. J. V., Botta, E., Stefanini, M., Egly, J. M., Aebersold, R., Hoeijmakers, J. H. J. & Vermeulen, W. (2004). "A new, tenth subunit of TFIIH is responsible for the DNA repair syndrome trichothiodystrophy group A". Nat. Genet. 36 (7): 714-9.

Li, J., Jin, W., Chen, Y., Di, G., Wu, J. and Shao, Z. M. (2008). "Genetic polymorphisms in the DNA repair enzyme ERCC2 and breast tumour risk in a Chinese population". The Journal of International Medical Research, 36(3).

Hoeijmakers, J. H. (2001). "Genome maintenance mechanisms for preventing cancer". Nature. 411(6835), 366-374.

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