The cell cycle is important for the duplication and the transmission of the genetic material to progeny cells. Cell cycle checkpoints are present which represent the restriction points between each phase of the cell cycle. The process can be halted to coordinate that each state will occur in the right sequence and in the right way before progression into the next phase (Kerzendorfer et all, 2009). DNA is constantly attacked by agents which come from the normal cell metabolism ( oxygen and free radicals) and by environmental agents (radiation and chemicals). This challenging will result in mutations, rearrangement and DNA breakage. DNA breakage consist of single strand breakage (SSB) and double strand breakage (DSB). DSB are the most detrimental. DNA breaks leads to chromosomal abbreviation (CA). The occurrence of CA is low in normal somatic cells and become higher in combination with the just mentioned agents. This event may cause tumor genesis by the inactivation of tumor suppressor genes or activation of once genes (Weinberg, 1988). There are two processes in which a cell could response to DNA damage; the signal transduction response (cell cycle arrest and apoptosis) and that of DNA damage repair. There is a network of repair mechanism present in all organisms to protect the DNA from several deficiencies. There are two repair mechanisms defined in eukaryotic cells with reference to DSB; the homologous recombination (HR) and the non-homologous and-joining (NHEJ) (Kuschel et al, 2002). The HR mechanism is the last resort for DNA repair and when HR genes become mutated or silenced this is characterized by gross gene rearrangements (Patel et all, 1998). Anti cancer therapies are used to induce DNA damage to kill the cancer cells. Radiotherapy is the second most common therapy after surgery. Cell death is caused by ionizing radiation and associated with DSB. There are several other anti cancer drugs that also induces DSBs (Topoisomerase 2 inhibitors and cross linkers such as Melphalan) and it is known that the ability of cancer cells to repair such DSBs determines the outcome of the treatment (Helleday, 2010). Recent studies have reported that promoter hypermethylation of HR genes is present in breast and ovarian tumors and thus become silenced (Esteller et all 2001). When HR genes become silenced or mutated it is known that these tumor cells are more sensitive to an anticancer drug. In this review I will shed light on the major genes involved in HR, the impact of HR on cancer with a particular focus on how HR can be used and which of this genes have hypermethylated promoters in cancer. When the promoter hypermethylation status of the HR is known, there could be other future anticancer therapies useful instead of radiation.
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The long and fragile DNA is constantly damaged by several agents which result in DSBs. There are two mechanism which are capable of repairing this DSBs; homology-dependent and -independent. The homology independent mechanism (NHEJ) is able to rejoin DSB ends end to end. The NHEJ is not error free , it often creates sequence alteration at the break site. In eukaryotes are both HR and NHEJ important while in yeast only the HR is primarily used (Gent et all, 2001). HR requires long sequence homologies of several hundred base pairs to restore the original sequence at the DSB site, this mechanism of DSB repair is error-free. HR is subdivided in conservative HR and non-conservative. Here, I will focus on the conservative HR mechanism. HR is found in meiosis where it has a function to create genetic diversity (Keeney, 2001) and in mitotic cells it has a function in the DSB repair. Conservative HR is also called gene conversion because the repair is achieved by copying the sequence information of the sister chromatid, resulting in two intact copies. After an DSB is induced, the 5'ïƒ 3' will be exonucleolytically resected to acquire long 3' single-stranded tails. This long single stranded tail invades the intact DNA duplex at the site of sequence homology. This invasion into the homologous strand result in the formation of a displacement-loop (D-loop). In this D-loop formation the 3' ends of the invading loop serve as primers for repair synthesis. DNA polymerase synthesize the new strands so that on new strand present in the donor and the recipient. This pairing is followed by formation of a Holliday junction intermediate, migration and resolution (Holliday, 1964). Endonucleolytic resolution resolve the junction to restore 2 linear DNA duplexes. HR in meiotic dividing cells results in gene conversion with cross-over. This crossing-over is the cause of HR between homologues. In mitotic cells HR is in most of the time without crossing over (factor 100-1000). HR in mitotic cells occur between identical sister chromatids so that the sequence that was present before the breakage is restored at the break side (Johnson, 2001). Identical sister chromatids are only present in late S phase and G2 phase when the chromosome is duplicated, for this reason is HR m active in late S phase and G2 phase mitotic cells.
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Genes involved in HR and their functions:
Many genes have been since the rapid development of several specific recombination assays
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Kerzendorfer, C. et all. (2009) Human DNA damage response and repair deficiency syndromes: linking genomic instability and cell cycle checkpoint proficiency. Elsevier, 8:1139-1152.
Patel, K.J. (1998) Involvement of BRCA2 in DNA repair. Mol. Cell, 1:347-357
Helleday, T. (2010) Homologous recombination in cancer development, treatment and development of drug resistance. Carciogenesis, 31:955-960
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