The WD repeats together form a β-propeller structure that directly binds BRCA2 ( 18), and the N-terminal coiled-coil motif was later found to directly bind BRCA1 ( 28, 41, 42). The PALB2 protein contains a coiled-coil domain at the N terminus and a series of WD repeats at its C terminus ( Fig. Finally, certain single nucleotide polymorphisms (SNPs) in the gene have been suggested to confer an increased risk of breast cancer ( 2). To date, dozens of truncating PALB2 mutations have been identified in cancer families around the world, causing moderate to very high risks of breast cancer ( 1, 26, 30). Furthermore, hypermethylation of the PALB2 promoter occurs in a significant fraction (∼7%) of both sporadic and familial breast/ovarian cancer cases ( 21). Later, PALB2 was also found to be mutated in familial pancreatic cancer, being the second most highly mutated pancreatic susceptibility gene after BRCA2 ( 7, 25). Immediately after its discovery, germ line truncating mutations in PALB2 were identified in familial breast cancer ( 4, 22, 31) and the N subtype of Fanconi anemia (FA-N) ( 23, 37). PALB2 was discovered as a major BRCA2 binding partner that controls its intranuclear localization, stability, recombinational repair, and DNA damage checkpoint functions ( 38). The two major high-penetrance breast cancer susceptibility genes BRCA1 and BRCA2 encode very large proteins with a critical function in homologous recombinational repair (HRR) of DNA double-strand breaks ( 15).
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