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...
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which in humans is encoded by the F ANCA gene, mutations in which are the most
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