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What Dna Repair Gene Causes Cancer

Written By Saturday, March 26, 2022 Add Comment Edit
  • Periodical Listing
  • J Mol Jail cell Biol
  • v.3(i); 2022 Feb
  • PMC3030973

J Mol Jail cell Biol. 2022 Feb; 3(ane): 51–58.

Epigenetic changes of DNA repair genes in cancer

Abstract

'Every Hour Hurts, The Concluding One Kills'. That is an former saying about getting former. Every day, thousands of DNA damaging events take place in each cell of our trunk, but efficient Dna repair systems have evolved to preclude that. However, our Dna repair organisation and that of most other organisms are not every bit perfect every bit that of Deinococcus radiodurans, for example, which is able to repair massive amounts of DNA damage at once. In many instances, accumulation of Deoxyribonucleic acid impairment has been linked to cancer, and genetic deficiencies in specific DNA repair genes are associated with tumor-prone phenotypes. In improver to mutations, which can be either inherited or somatically acquired, epigenetic silencing of DNA repair genes may promote tumorigenesis. This review will summarize current knowledge of the epigenetic inactivation of unlike Dna repair components in human cancer.

Keywords: DNA methylation, DNA repair, epigenetics

Introduction

Cancer is characterized past uncontrolled malignant growth and prison cell partitioning. Cancer cells have a higher proliferation rate than their corresponding normal tissue and they often have lost the ability to undergo programmed cell death (apoptosis). Furthermore, they tin can learn the capability to separate from their original tissue and tin can develop metastasis in other regions of the trunk. Major causes of matted cellular programming in cancer are genetic and epigenetic changes. For case, point mutations, deletions, duplications, insertions, translocations, chromosome aberrations, viral infections, and epigenetic inactivation represent various types of potentially cancer-causing events. These mechanisms may affect the Deoxyribonucleic acid sequence and/or may change the role and regulation of the gene products or lead to a loss of function.

A special subset of cancer-relevant genes is represented by deregulated tumor suppressor genes and oncogenes. Genetically changed or over-expressed protooncogenes (oncogenes) promote aberrant cell growth and the products of tumor suppressor genes commonly control jail cell division and genetic stability. Tumor suppressor genes controlling cell growth are disquisitional, just their importance is probably equal to that of genes involved in DNA repair systems. Constructive Dna repair is at the backbone of cancer-free survival. Mutations in DNA repair genes of the nucleotide excision repair (NER) grouping (XP genes in xeroderma pigmentosum patients), mutations affecting the mismatch repair (MMR) genes [in patients with inherited colorectal cancer (CRC) predisposition], Dna crosslink repair (Fanconi anemia genes), and several others are the cause of inherited cancer syndromes. As an alternative mechanism to genetic mutation, a Dna repair system may be inactivated or decreased in effectiveness by epigenetic cistron inactivation mechanisms affecting DNA repair genes. In this review, we will discuss some examples of such mechanisms in specific human cancers (summarized in Table1).

Table 1

Methylated DNA repair genes in cancer.

Repair arrangement Genes Known cancer types
Base excision repair (BER) MBD4 Colorectal cancer (jail cell lines), ovarian cancer (cell lines) (Howard et al., 2009), multiple myeloma (cell lines) (Peng et al., 2006)
TDG Multiple myeloma (cell lines) (Peng et al., 2006)
OGG1 Thyroid cancer (jail cell lines and tumors) (Guan et al., 2008)
Direct reversal of DNA damage MGMT Colon cancer (Herfarth et al., 1999), gastric carcinoma (Oue et al., 2001), glioblastoma (Esteller et al., 2000), head and neck squamous jail cell carcinoma (cell lines) (Goldenberg et al., 2004), not-small jail cell lung cancer (Wolf et al., 2001)
Nucleotide excision repair (NER) XPC Bladder cancer (Yang et al., 2022)
RAD23A Multiple myeloma (cell lines) (Peng et al., 2005)
ERCC1 Glioma (cell lines and tumors) (Chen et al., 2022)
Mismatch excision repair (MMR) MLH1 Acute myeloid leukemia (Seedhouse et al., 2003), gastric cancer (Fleisher et al., 1999), neck squamous cell carcinoma (Liu et al., 2002), non-small prison cell lung cancer (Wang et al., 2003), oral squamous cell carcinoma (Czerninski et al., 2009), ovarian cancer (Gras et al., 2001a), desultory colorectal cancer (Kane et al., 1997), sporadic endometrial carcinoma (Esteller et al., 1998)
MSH2 Colorectal cancer (Lawes et al., 2005), not-small cell lung cancer (Wang et al., 2003), oral squamous jail cell carcinoma (Czerninski et al., 2009), ovarian cancer (Zhang et al., 2008)
MSH3 Gastric carcinoma (in elderly) (Kim et al., 2022), sporadic colorectal cancer (Benachenhou et al., 1998)
MSH6 Colorectal cancer (Lawes et al., 2005)
Homologous recombination BRCA1 Breast cancer (Dobrovic and Simpfendorfer, 1997), ovarian cancer (Catteau et al., 1999), gastric cancer (Bernal et al., 2008), not-small prison cell lung cancer (Lee et al., 2007), uterine cancer (Xing et al., 2009), bladder cancer (Yu et al., 2007)
Not-homologous finish-joining XRCC5 Non-small cell lung cancer (Lee et al., 2007)
Editing and processing nucleases FEN1 Breast cancer (hypomethylated) (Singh et al., 2008)
Genes defective in diseases associated with sensitivity to Dna damaging agents WRN Breast cancer (prison cell lines and tumors), colon cancer (cell lines), colorectal cancer, gastric cancer, leukemia (cell lines), non-modest cell lung cancer, prostate cancer, thyroid cancer (Agrelo et al., 2006)
ATM Chest tumors (non confirmed) (Vo et al., 2004; Treilleux et al., 2007; Flanagan et al., 2009), colorectal cancer (cell lines) (Kim et al., 2002), head and cervix squamous jail cell carcinoma (Ai et al., 2004)
Fanconi anemia FANCC Desultory leukemia (0.seven–3.one%) (Hess et al., 2008)
FANCF Cervical cancer (Narayan et al., 2004), head and neck squamous cell carcinoma, not-small cell lung cancer (Marsit et al., 2004), ovarian cancer (cell lines and tumors) (Olopade and Wei, 2003)
FANCL Desultory leukemia (∼i%) (Hess et al., 2008)
Other conserved DNA damage response genes CHK2 Glioma (Wang et al., 2022), not-small jail cell lung carcinoma (cell lines and tumors) (Kim et al., 2009)

Epigenetic mechanisms in gene regulation

Epigenetic mechanisms are used in many different ways for control of gene expression. Epigenetic changes never involve a change in the master Dna sequence or a modify in base pairing but are reflected primarily in DNA cytosine modification patterns, histone postal service-translational modifications, or degradation of certain histone variants forth specific factor sequences. These epigenetic modifications of genes are generally reversible, but can get transmitted to the daughter cells (Laird, 2005). For example, one type of epigenetic change that tin can occur is that the chromatin structure changes from an open up agile configuration, likewise referred to as euchromatin, to a densely packed inactive chromatin structure, the so-called heterochromatin.

Ane mutual and perhaps the most permanent and stable machinery of epigenetic factor inactivation is the methylation of the v-carbon of the DNA base cytosine in the 5′-CpG-3′ dinucleotide sequence context of CpG island or promoter regions. These methylation reactions carried out by DNA cytosine methyltransferases are a primary component of epigenetic regulatory mechanisms in mammals (Baylin et al., 2001). In tumor tissues, tumor suppressor genes are oft inactivated epigenetically by methylation when compared with normal tissue. The DNA methylation events are oft preceded past changes in chromatin construction and histone modifications, for case, by loss of the active histone mark H3K4 trimethylation (Figurei). Sequences that have undergone Deoxyribonucleic acid methylation oft harbor repressive histone modifications such as H3K9 trimethylation.

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Epigenetic inactivation of a DNA repair cistron promoter. Promoters are oftentimes embedded inside CpG islands. These CpG-rich sequences are unremarkably unmethylated in normal tissues and are associated with the active histone mark H3K4me3. H3K4me3 prevents Deoxyribonucleic acid methylation. During tumorigenesis, the CpG island becomes methylated, is associated with inactive chromatin marks (e.1000. H3K9me3), and the gene becomes silenced.

Epigenetic inactivation of Dna repair genes

Ii major types of DNA repair exist. The first i repairs DNA damage that arises from external sources such as UV light or ionizing rays and from endogenous Deoxyribonucleic acid damage, for case, due to oxidative stress. To this type of repair belong the base excision repair (BER) pathway, the direct reversal of DNA damage, and the NER pathways. The other general mechanism of repair deals with the mistakes made during Deoxyribonucleic acid replication. This organization includes factors involved in MMR, homologous recombination, sure Dna helicases, editing and processing nucleases, and other genes, which are lacking in diseases associated with sensitivity to Deoxyribonucleic acid damaging agents (Jackson and Bartek, 2009; Ciccia and Elledge, 2022).

Base excision repair

In BER, by and large a single damaged DNA base is removed by a DNA glycosylase-type enzyme. The resulting abasic site is then repaired past additional steps including Deoxyribonucleic acid backbone incision, gap filling, and ligation. The most common mutation institute in human genetic diseases and cancer is the C to T transition mutation found at CpG dinucleotides. These mutations are thought to ascend from deamination of five-methylcytosine (Pfeifer, 2006). The methyl-CpG bounden domain protein 4 (MBD4; also known as MED1) has the power to bind methylated Deoxyribonucleic acid (Hendrich and Bird, 1998), and furthermore, it preferentially binds to the T:Chiliad mismatches at CpG sites (Hendrich et al., 1999). These mismatches are the product of deamination of methylated CpGs. MBD4 has a glycosylase domain and is able to repair these mismatches by removing thymine from Deoxyribonucleic acid (Hendrich et al., 1999). MBD4 has the same function as the thymine Dna glycosylase (TDG) poly peptide (Wiebauer and Jiricny, 1989; Yoon et al., 2003). Thus, MBD4 and TDG belong to a group of BER enzymes likely to exist important for counteracting a procedure of endogenous DNA impairment, hydrolytic deamination of v-methylcytosine. For these two DNA repair genes, MBD4 and TDG, promoter methylation has been found in different cancer types. Several multiple myeloma cell lines (KAS-vi/one, KMS-xi, OPM2, KMS-12, and JIM3) showed promoter methylation and decreased gene expression compared with normal plasma cells for TDG (Peng et al., 2006). MBD4 is significantly methylated in CRC prison cell lines and ovarian cancer (OC) prison cell lines (Howard et al., 2009). In sporadic CRC, promoter methylation of MBD4 is an early effect in tumorigenesis and could exist used every bit a prognostic gene.

Some other BER gene for which promoter methylation has been constitute is OGG1. OGG1 repairs oxidatively damaged guanine bases in DNA and mutations of this gene may be involved in tumorigenesis (Arai et al., 1997; Chevillard et al., 1998; Shinmura and Yokota, 2001). But at this point, a methylated promoter of OGG1 is only known in 5% of thyroid cancer and in some thyroid cancer cell lines (Guan et al., 2008).

Straight reversal of Dna damage

MGMT encodes the Ovi-methylguanine-Deoxyribonucleic acid methyltransferase (Tano et al., 1990; Natarajan et al., 1992). This enzyme repairs Dna alkylation damage. Alkylation reactions pb to formation of a methyl group (CH3-) at the O6 position of guanine. Ohalf dozen-methylguanine pairs with thymine rather than cytosine and promotes G:C to A:T mutations. MGMT repairs this damage and protects the DNA by transferring the methyl group to a cysteine residue in the protein. Epigenetic inactivation by promoter methylation of the MGMT gene is very well established. This factor is epigenetically silenced in a variety of cancers (Esteller et al., 1999). Specifically, MGMT methylation is found in glioblastomas (Esteller et al., 2000; Mellai et al., 2009; Shamsara et al., 2009), colon cancer (Herfarth et al., 1999; Ogino et al., 2007), not-small cell lung cancer (NSCLC) (Wolf et al., 2001; Wu et al., 2008), gastric carcinoma (Oue et al., 2001), head and cervix squamous cell carcinoma (HNSCC) (Goldenberg et al., 2004; Maruya et al., 2004; Steinmann et al., 2009), and many other cancer types. Interesting is the fact that glioma patients with a methylated and inactivated MGMT cistron who were treated by chemotherapy with alkylating agents, such as temozolomide, have a improve survival relative to patients with an unmethylated and active MGMT gene (Esteller et al., 2000; Hegi et al., 2005; Kaina et al., 2007).

Nucleotide excision repair

The NER organization consists of two sub-pathways. The global genome repair (GGR) mechanism repairs DNA damage in transcriptionally inactive parts of the genome (Sugasawa et al., 2001; Riedl et al., 2003). The second NER component is responsible for repair of transcribed DNA and is referred to equally transcription-coupled repair (TCR) (Fousteri and Mullenders, 2008; Hanawalt and Spivak, 2008). These two NER functions differ in the damage recognition step. The poly peptide encoded by the xeroderma pigmentosum grouping C (XPC) cistron is a subunit of these harm recognition complexes and is essential for GGR (Friedberg, 2001; Riedl et al., 2003). For the TCR pathway, recognition of the Dna damage-blocked RNA polymerase by transcription-repair coupling factors is important. After damage recognition, the GGR and TCR have the same or like subsequent steps involved in nucleotide excision and gap filling.

Using a luciferase assay, Wu et al. (2007) establish that the promoter region −175 to −1 upstream of the XPC gene is important for the regulation of this factor. Furthermore, they found that in different cell lines (Calu-1, H1355, and H441), this region is highly methylated and methylation regulates the expression level of XPC. The first example for a chief tumor characterized by XPC gene methylation was bladder cancer (methylation level of 32.4% in bladder cancer versus 6.1% in normal tissue) (Yang et al., 2022). In addition, it is known that 2 other genes, which are role of the NER organization, are methylated in human tumors. The genes RAD23A and ERCC1, which are involved in Dna harm recognition and incision, respectively, are also inactivated through promoter methylation. The RAD23A gene is methylated in the multiple myeloma cell line KAS 6/1 (Peng et al., 2005) and ERCC1 is methylation-silenced in glioma cell lines and glioma tumors (Chen et al., 2022).

Mismatch excision repair

The Dna MMR protein MLH1 is encoded by the MutL homolog 1 (MLH1) factor in humans and is a homologue of the DNA MMR factor mutL of Escherichia coli. The MMR office is associated with DNA replication, to correct for deficiencies in Deoxyribonucleic acid polymerase proofreading function. A missing gene or mutations of this gene and other MMR genes (MSH2, MSH6, or PMS2) leads to microsatellite instability (MSI) and this dysfunction is highly associated with hereditary non-polyposis colon cancer (HNPCC or Lynch syndrome) (Bronner et al., 1994).

It has been shown that methylation in the promoter region of MLH1 correlates with decreased activity of the gene (Kane et al., 1997). Next to the main cancer type where this factor is inactivated, HNPCC, this gene is epigenetically inactivated besides in other types of cancer, for instance, in sporadic endometrial carcinoma (Esteller et al., 1998), gastric cancers (Fleisher et al., 1999), sporadic CRC (Kane et al., 1997; Herman et al., 1998), ovarian tumors (Gras et al., 2001a), NSCLC (Wang et al., 2003), oral squamous cell carcinoma (SCC) (Czerninski et al., 2009), neck SCC (Liu et al., 2002; Steinmann et al., 2009), and acute myeloid leukemia (AML) (Seedhouse et al., 2003). Constitutional methylation of the MLH1 gene, characterized by soma-broad methylation of a unmarried allele and transcriptional silencing, has been identified in a subset of Lynch syndrome cases lacking a sequence mutation in MLH1 (Gazzoli et al., 2002; Suter et al., 2004; Hitchins et al., 2007). This particular instance provides potent support for the proposal that methylation of a DNA repair gene tin can be a crucial mechanism in carcinogenesis.

Several other genes vest to the MMR system. The activity of the genes coding for MutS homologues ii, iii, and 6 (MSH2, MSH3, and MSH6) is too controlled past promoter methylation. The office of these gene products is in mismatch recognition. MSH2, for example, is methylated in CRC (Lawes et al., 2005; Nagasaka et al., 2022), primary NSCLC (Wang et al., 2003), oral SCC (Czerninski et al., 2009), and OC (Zhang et al., 2008). MSH2 is besides highly methylated in neurofibromatosis type i (Titze et al., 2022). Further, information technology has been found that methylation occurs in CRC in the promoter region of MSH6 (Lawes et al., 2005). For MSH3, it was found that it is epigenetically inactivated in desultory CRC (Benachenhou et al., 1998). In elderly gastric carcinoma patients, MSH3 was significantly more methylated than in younger patients (Kim et al., 2022). In conclusion, methylation of the gene MLH1 may have considerable importance in cancer development and as a prognostic factor and the genes MSH2, MSH3, and MSH6 are interesting candidates besides.

Homologous recombination

If information technology is not possible to repair the Deoxyribonucleic acid damage before replication, the Dna may be repaired by homologous pairing. Because of DNA polymerase-blocking damage, Deoxyribonucleic acid strand breaks will exist generated, which can be repaired past the homologous recombination repair arrangement. The BRCA1 and BRCA2 (Breast Cancer 1 and two) proteins are involved in this repair pathway. The BRCA1 and BRCA2 genes are tumor suppressor genes and the proteins, together with RAD51, class a complex to repair Dna strand breaks (Duncan et al., 1998; Yoshida and Miki, 2004). These genes are characterized by tumor-specific mutations in inherited breast and OC (Miki et al., 1994; Wooster et al., 1994; Narod, 2022). A few years subsequently their initial discovery, researchers plant promoter methylation for BRCA1 which correlated with low mRNA levels (Dobrovic and Simpfendorfer, 1997). For BRCA2, information technology has been found that a low mRNA level is by and large not acquired past hypermethylation of the promoter (Gras et al., 2001b; Hilton et al., 2002). BRCA1 is most often methylated in breast and OC but also in gastric cancer (Bernal et al., 2008), NSCLC (Lee et al., 2007), uterine cancer (Xing et al., 2009), and bladder cancer (Yu et al., 2007).

Non homologous cease-joining

The gene production of XRCC5 is the protein K80 (Taccioli et al., 1994). Together with the gene product of XRCC6, it forms the 80 and 70 kDa subunits of the K70/K80 heterodimer protein Ku, which is involved in the binding of double-strand breaks (DSBs) during non-homologous end-joining (Difilippantonio et al., 2000; Koike, 2002). Together with the Deoxyribonucleic acid-PKcs (Deoxyribonucleic acid-dependent protein kinase catalytic subunit), the Ku heterodimer forms the total complex DNA-PK (Carter et al., 1990). At this time, an epigenetic inactivation of this pathway of Deoxyribonucleic acid repair is just known for the gene XRCC5 (Lee et al., 2007). The authors showed that 21% of all NSCLCs were methylated in the promoter region of XRCC5. Furthermore, 15% of adenocarcinomas and 32% of SCCs were methylated and had a low protein expression level (Lee et al., 2007). This area of enquiry should be extended into other types of cancer to see whether XRCC5 or other genes of this pathway may play an important part every bit targets of epigenetic silencing.

Editing and processing nucleases

FEN1 codes for the flap construction-specific endonuclease 1 (too known as DNase Iv) and is a five′-nuclease (Hiraoka et al., 1995). This protein is important for the processing of the five′ ends of Okazaki fragments during lagging strand Dna synthesis (Henneke et al., 2003) and removes the 5′ flaps during long-patch BER (Klungland and Lindahl, 1997). FEN1 may be involved in the repair of DNA DSBs by non-homologous end-joining (Wu et al., 1999) and homologous recombination (Kikuchi et al., 2005). Furthermore, it is important for genomic stability (Singh et al., 2007).

FEN1 is highly expressed in proliferative tissues such as bone marrow, testes, and thymus (Otto et al., 2001) and is over-expressed in testis, lung, and brain tumors (Nikolova et al., 2009) and in prostate cancer (Lam et al., 2006), metastatic prostate cancer cells (LaTulippe et al., 2002), neuroblastomas (Krause et al., 2005), and pancreatic cancer (Iacobuzio-Donahue et al., 2003). FEN1 expression is also increased in lung cancer jail cell lines (SCLC and NSCLC) (Sato et al., 2003) and gastric cancer cell lines (Kim et al., 2005).

These data indicate that an increased expression level of FEN1 leads to cancer or is associated with cancer. It has been shown that not epigenetic inactivation simply rather an absence of methylation (Deoxyribonucleic acid hypomethylation) of FEN1 is associated with breast cancer (Singh et al., 2008). Compared with normal tissue with a 57.6% methylation level, the methylation level in breast tumors was only 1.ii% (Singh et al., 2008). Considering of the many cancer types, where FEN1 expression is increased, this finding gives a useful hint to look for additional epigenetic changes affecting this gene in other cancer types.

Genes defective in diseases associated with sensitivity to DNA-damaging agents

Werner syndrome is an autosomal recessive disorder. It is characterized by accelerated aging of the mesodermal tissue. The responsible gene (WRN) is a DNA helicase and a RecQ family fellow member (Gray et al., 1997). The WRN gene is methylated in a large number of different cancer types. Examples are prison cell lines from colon cancer, breast cancer, and leukemia, and information technology is almost highly methylated in principal tumor samples of CRC (37.9%), NSCLC (37.5%), gastric cancer (25%), prostate (20%), breast (17.two%), and thyroid (12.v%) (Agrelo et al., 2006; Kawasaki et al., 2008).

The product of the Ataxia telangiectasia mutated (ATM) factor is a serine protein kinase and tumor suppressor. When a DNA DSB has been generated, cell bicycle arrest is initiated by the ATM signaling network. Afterward an initial finding that CRC prison cell lines are methylated at the ATM gene (Kim et al., 2002), it has been plant that likewise primary breast tumors are very often methylated (78%) (Vo et al., 2004). But these high methylation frequencies do not seem to be a full general finding in breast cancer. One group could not confirm these results (Treilleux et al., 2007). Some other group could show that ATM is methylated in blood samples of breast cancer patients (Flanagan et al., 2009). Therefore, the relevance of ATM gene methylation in breast cancer is not clear. Furthermore, ATM is significantly methylated (25%) in HNSCCs (Ai et al., 2004).

Fanconi anemia

Fanconi anemia is an autosomal recessive genetic disorder. Thirteen genes are associated with this disease. These genes are DNA repair genes and mutation of each of them leads to the same disorder. The genes are called Fanconi anemia, complementation group A, B, C, D1, D2, E, F, Grand, I, J, L, 1000, and N (FANCA-Northward). Assembly of a circuitous of FANC proteins is activated past replicative stress, particularly Dna impairment caused by cross-linking agents. At this fourth dimension, epigenetic inactivation is merely known for a few of these genes. Methylation of FANCF is mostly observed in principal OC and cell lines (Olopade and Wei, 2003). The range of promoter methylation was betwixt 21% (Olopade and Wei, 2003) and 24% (Dhillon et al., 2004) and upwards to 27.viii% (Wang et al., 2006) in main tumors. One event showed only xiii.2% methylation frequency (Lim et al., 2008). Furthermore, promoter methylation was found in NSCLC with 14% and in HNSCC with 15% (Marsit et al., 2004). A loftier methylation rate of FANCF was also found in cervical cancer with thirty% (Narayan et al., 2004). In dissimilarity to these findings, no or only very rare promoter methylation was constitute in breast cancer (Wei et al., 2008; Tokunaga et al., 2009). Additionally, very minimal promoter methylation was found in the genes FANCC and FANCL in sporadic acute leukemia. AML showed a 0.7% methylation frequency for FANCC; in acute lymphoblastic leukemia (ALL), the methylation frequency was 3.1% for FANCC and the gene FANCL was methylated in one% of ALL cases (Hess et al., 2008). In general, not much is known about epigenetic inactivation of this whole gene family unit in cancer.

Other conserved Dna harm response genes

The last interesting candidate is the CHK2 checkpoint homologue (CHK2). CHK2 is a protein kinase functioning in an important DNA impairment response pathway and is involved in regulation of cell cycle arrest (Matsuoka et al., 1998). Information technology has been shown that this factor is inactivated past promoter methylation in NSCLC with 28.1% tumor methylation frequency in total (squamous cell lung carcinoma 40%; adenocarcinoma 19%) (Kim et al., 2009) and in NSCLC jail cell lines (Zhang et al., 2004). In gliomas, CHK2 is methylated in the proximal CpG isle promoter and is significantly downwardly-regulated (Wang et al., 2022). For breast cancer, colon cancer, and OC, it has been shown that methylation in the proximal CpG island in tumors as well as in normal tissue has no influence on cancer progression (Williams et al., 2006). The distal CpG island is unmethylated in these cancer types (Williams et al., 2006). Additionally, no methylation in breast cancer was constitute (Sullivan et al., 2002). In conclusion, this gene shows some interesting findings and it may be worth to await for CHK2 methylation in other cancer types.

Conclusions

Epigenetic inactivation of Dna repair genes in cancer has been reported for several Deoxyribonucleic acid repair pathways including BER, NER, DNA MMR, and several other Deoxyribonucleic acid damage processing mechanisms. Within ane Dna repair pathway, specific genes are oft preferentially methylated. It remains to exist determined whether this specificity is due to selection of particular repair gene silencing events in promoting tumorigenesis or is due to preferential targeting of the Deoxyribonucleic acid methylation machinery to specific DNA repair cistron promoters.

It can exist causeless that these epigenetic inactivation processes can consequence in an increment in genetic instability during tumorigenesis that tin can be directly attributed to the deficiencies in DNA repair. Therefore, inactivation of DNA repair genes can be seen every bit an important effect in cancer initiation and/or progression by reducing genomic stability leading to genetic aberrations at other important gene loci. Such a mechanism is proven for inactivation of MMR pathways in colorectal tumors but awaits straight confirmation for a number of other DNA repair genes that are constitute methylated in tumors. On the other hand, diminished DNA repair is expected to pb to reduced cell survival in general, and additional events are likely occurring that enable a cell with reduced repair capacity to undergo uncontrolled proliferation instead of cell death (e.k. mutation in TP53). Interestingly, reduced repair capacity for alkylated guanines past promoter methylation of the MGMT gene has provided a therapeutic benefit in patients with glioma (Esteller et al., 2000). Conversely, inactivation of the MMR system has been associated with resistance of cells to cisplatinum treatment (Fink et al., 1997). With ever-increasing knowledge of the epigenome of specific cancer types, in that location is at present the opportunity to develop chemotherapy regimens tailored to a patient'southward DNA repair gene status past incorporating information on epigenetic silencing of the relevant genes in the tumor.

Disharmonize of interest: none alleged.

Funding

Work of the authors was supported past NIH grant ES06070 to G.P.P.

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