Abstract
Among human genetic diseases, Fanconi Anemia (FA) tops all with its largest number of health complications in nearly all human organ systems, suggesting the significant roles played by FA genes in the maintenance of human health. With the accumulated research on FA, the encoded protein products by FA genes have been building up to the biggest cell defense signaling network, composed of not only 22+ FA proteins but also ATM, ATR, and many other non-FA proteins. The FA D2 group protein (FANCD2) and its paralog form the focal point of FA signaling to converge the effects of its upstream players in response to a variety of cellular insults and simultaneously with downstream players to protect humans from contracting diseases, including aging and cancer. In this review, we update and discuss how the FA signaling crucially eases cellular stresses through understanding its focal point.
Highlights
Fanconi anemia (FA) is a rare human genetic disorder with an incidence rate of about one in 136,000 births, and half of Fanconi Anemia (FA) patients are diagnosed prior to age 10 [1,2,3,4,5]
We discovered that a new form of FANCL protein, named FAVL, dysregulates the FA signaling in non-FA human tumor cells and acts as a tumor promoting factor by inactivating FANCD2 and FANCI/the ID complex [79,80,81,82]
Upon activation of the master replication checkpoint kinase ATR, FANCD2 and FANCI accumulate within chromatin in the vicinity of replication forks, and FANCD2 associates transiently with the replication machineries
Summary
Fanconi anemia (FA) is a rare human genetic disorder with an incidence rate of about one in 136,000 births, and half of FA patients are diagnosed prior to age 10 [1,2,3,4,5]. FA occurs in males and females and is found in all ethnic groups, but is more common among people of Ashkenazi Jewish descent, the Roma population of Spain, and black South Africans [3,4] It is usually inherited as an autosomal recessive genetic disorder, but X-linked or autosomal-dominant inheritance has been reported. Noting many published reviews on the relation between FA signaling and human diseases [1,2,3,4,5,6,9,10], we highlight how the FA proteins, located at the center of FA signaling, orchestrate all players involved in this signaling network to advance our understanding of cancer development and treatment
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