Welcome to the newly established Howlett Laboratory at the University of Rhode Island in Kingston. We are interested in understanding the etiology of the rare recessive disease Fanconi anemia (FA). FA is characterized by developmental defects, bone marrow failure, and an increased susceptibility to cancer.
FA is a rare hereditary disease characterized by developmental defects, hematological deficiencies and increased susceptibility to cancer, including acute myelogenous leukemia (AML) and solid tumors of the head and neck and gynecological regions. FA is a rare, predominantly autosomal recessive disorder (FA-B is caused by mutation in the X-linked FANCB gene), with a prevalence of approximately 1-5 affected individuals per million. There are currently approximately 300 known affected individuals in the US. FA patient derived cells are hypersensitive to DNA cross-linking agents such as mitomycin C and cisplatin.
There are currently thirteen defined FA complementation groups (A, B, C, D1/BRCA2, D2, E, F, G, I, J/BRIP1, L, M, and N/PALB2) and the genes underlying twelve of these complementation groups have been cloned. The FA proteins and the BReast Cancer-Associated proteins BRCA1 and BRCA2 interact in a common pathway essential in the cellular DNA damage response. The FA proteins A, B, C, E, F, G, L, and M assemble in a multi-subunit nuclear complex. Following exposure to DNA damaging agents, and also during S phase of the cell cycle, the core FA complex activates the mono-ubiquitination of lysine 561 of the FANCD2 protein, signaling its activation and translocation to discrete nuclear foci where it co-localizes with the key DNA repair proteins BRCA1 and RAD51. Mono-ubiquitination of FANCD2 promotes loading of the BRCA2 protein into chromatin complexes, and facilitates the assembly of DNA damage inducible RAD51 nuclear foci. However, the exact biochemical function of chromatin-associated mono-ubiquitinated FANCD2 protein remains unclear.