Fanconi Anemia (FA) is a hereditary recessive disorder that is characterized by defective DNA cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and cytogenetic instability. FA is caused by mutations in a complex set of proteins, including a FA core complex which contains eight out of sixteen known FA genes and their associated proteins. The FA proteins work together in a genome maintenance pathway called the FA/BRCA pathway, which plays an important role during the S phase of the cell cycle. The list FA complementation group (FANC) are: FANC-A, -B, -C, -D1/BRCA2, -D2, -E, -F, -G, -L, -I, -J/BRIP1,-M, -N/PALB2, -P/SLX4, -O/RAD51C and XPF. While the members of the FA complementation group do not share sequence similarity, they are related by their assembly into a common nuclear protein complex. Beside these sixteen FA proteins, there are several other proteins associating with the FA core complex, known as the FA Associated Proteins (FAAPs): -100, -24, -20, -16/MHF1, and -10/MHF2. FA plays an important role in the genomic stability through DNA repair of interstrand crosslinks (ICLs). When mutations occur in these genes, however, abnormal cell division, which eventually causes cancer and congenital defects occurs in most patients (Nalepa, et al., 2013; Tomida, et al., 2013).
Fanconi anemia is caused by mutations in one of the Fanconi anemia genes leading to lack of interstrand crosslink repair. In the process of DNA repairing, the interstrand crosslinks is recognized by the complex of two proteins, FAAP24 and FANCM. These proteins participate in substrate binding and enable recruitment of the FA core complex. This core has E3 ligase activity and can monoubiquitinate (addition of o...
... middle of paper ...
...d DNA damage response pathway. EMBO J. 26: 2104–2114.
Nalepa G, Enzor R, Sun Z, Marchal C, Park SJ, Yang Y, Tedeschi L, Kelich S, Hanenberg H and
Clapp DW. 2013. Fanconi anemia signaling network regulates the spindle assembly checkpoint. J. Clin. Invest. 13:3829-3847.
Tomida J, Itaya A, Shigechi T, Unno J, Uchida E, Ikura M, Masuda Y, Matsuda S, Adachi J, Kobayashi M, Meetei AR, Maehara Y, Yamamoto K, Kamiya K, Matsuura A, Matsuda T, Ikura T, Ishiai M and Takata M. 2013. A novel interplay between the Fanconi anemia core complex and ATR-ATRIP kinase during DNA cross-link repair. Nucleic Acids Res. 41: 6930-6941.
Wienk H, Slootweg JC, Speerstra S, Kaptein R, Boelens R, and Folkers GE. 2013. The Fanconi anemia associated protein FAAP24 uses two substrate specific binding surfaces for DNA recognition. Nucleic Acids Res. 41: 6739–6749.
Suresh, G., Horbar, J., Plsek, P., Gray, J., Edwards, W., Shiono, P., & ... Goldmann, D. (2004).
Stanley, J., Gannon, J., Gabuat, J., Hartranft, S., Adams, N., Mayes, C., Shouse, G. M.,
Nowicka, P., Santoro, N., Liu, H., Lartaud, D., Shaw, M. M., Goldberg, R., Guandalini, C.,
Zhang, Y. B., Harwood, J., Williams, A., Ylänne-McEwen, V., Wadleigh, P. M., & Thimm, C.
9.Wang, P. S., Gruber, M. J., Powers, R. E., Schoenbaum, M., Speier, A. H., Wells, K. B., &
The most common way of getting Angelman syndrome is through chromosome deletion. This is responsible for about 68% of all cases o...
...l electrophoresis (SCGE) also known as comet assay has become one of the standard methods for assessing DNA damage, with applications ranging from testing genotoxicity, human bio-monitoring and molecular epidemiology to its use in fundamental research in DNA damage and repair (Collins, 2004). The comet assay is a simple method for detecting DNA strand breaks within cells in eukaryotes. The procedure of comet assay includes Embedding the cells in agarose in a microscope slide, followed by lysing of cells with detergent and high salts to form nucleotides containing supercoiled loops of DNA linked to the nuclear matrix, and then undergoing Electrophoresis at high pH, which results in formation of structures resembling as comets, observed by fluorescence microscopy. The intensity of the comet tail relative to the head reflects the number of DNA breaks (Collins, 2004).
The cell cycle is the process by which cells progress and divide. In normal cells, the cell cycle is controlled by a complex series of signaling pathways by which a cell grows, replicates it’s DNA and divides, these are called proto-oncogenes. A proto-oncogene is a normal gene that could become an oncogene due to mutations. This process has mechanisms to ensure that errors are corrected, if they are not, the cells commit suicide (apoptosis). This process is tightly regulated by the genes within a cell’s nucleus. In cancer, as a result of genetic mutations, this process malfunctions, resulting in uncontrolled cell proliferation. Mutations in proto-oncogene or in a tumour suppressor gene allow a cancerous cell to grow and divide without the normal control imposed by the cell cycle. A change in the DNA sequence of the proto-oncogene gives rise to an oncogene, which
Ottenberg, A. L., Wu, J. T., Poland, G. A., Jacobson, R. M., Koenig , B. A., & Tilburt, J. C.
Signatures 2, 4, 5, 13, and 16 showed significant contributions. Signature 4 is classified by C > A base mutations, and was found to likely be the consequence of misreplication of DNA damage from carcinogens. Signatures 2 and 13 are made up by C>T and C>G mutations, but they were only shown more in smokers than nonsmokers in lung cancer, while still being present in the other cancer types, unrelated to tobacco smoking. Signature 5 is characterized by mutations across all 96 subtypes of base substitution and is found in all cancer types. It occurs widespread in nonsmokers and in cancers unrelated to smoking; therefore, it can be concluded that it is probably not a direct consequence of misreplication of DNA damaged from carcinogens. Signature 16 is characterized by T>C mutations and was only increasingly detected in liver cancer for smokers versus nonsmokers, but its mechanism is
Kobau, R., Zack, M. M., Manderscheid, R., Palpant, R. G., Morales, D. S., Luncheon, C., et al.
Nicklas, T., Jahns, L., Bogle, M., Chester, D., Giovanni, M., Klurfeld, D., Laugero, K., Liu, Y.,
Zosuls, K. M., Ruble, D. N., Tamis-LeMonda, C. S., Shrout, P. E., Bornstein, M. H., & Greulich,
which in humans is encoded by the F ANCA gene, mutations in which are the most
Timpano, K. R., Keough, M. E., Mahaffey, B., Schmidt, N. B., & Abramowitz, J. (2010).