Assembling an orchestra: Fanconi anemia pathway of repair

Abstract

Fanconi anemia (FA) is a recessive genetic disorder characterized by developmental defects, bone marrow failure, and cancer susceptibility. The complete set of FA genes has only been identified recently and seems to be uniquely conserved among vertebrates. Fanconi anemia proteins have been implicated in the repair of interstrand DNA crosslinks that block DNA replication and transcription. Although all thirteen FA complementation groups show similar clinical and cellular phenotypes, approximately 85% of patients presented defective FANCA, FANCC, or FANCG. The established DNA interacting components (FANCM, FANCI, FANCD2, and FANCJ) account only for approximately 5% of all FA patients, an observation that raises doubt concerning the roles of FA proteins in DNA repair. In recent years, rapid progress in the area of FA research has provided great insights into the critical roles of FA proteins in DNA repair. However, many FA proteins do not have identifiable domains to indicate how they contribute to biological processes, particularly DNA repair. Therefore, future biochemical studies are warranted to understand the biological functions of FA proteins and their implications in human diseases.

Rad5-dependent DNA Repair Functions of the Saccharomyces cerevisiae FANCM Protein Homolog Mph1

“…Furthermore, the epistatic spontaneous CAN1 forward mutation rates (Table 1) suggest that Mph1 is upstream of Chl1 as would be expected based on the human pathway (47).…”

Fanconi Anemia Complementation Group A (FANCA) Protein Has Intrinsic Affinity for Nucleic Acids with Preference for Single-stranded Forms

“…FA proteins have been generally believed to be involved in the repair of DNA ICLs that block replication and transcription (1)(2)(3)(4)(5)(6)(7)(8)(9). Although there are at least 15 FA disease-causing genes, ϳ60% of the disease is caused by a deficiency in FANCA (8, 18).…”

“…3 is an autosomal recessive or X-linked disorder characterized by bone marrow failure, developmental abnormalities, predisposition to cancer, and hypersensitivity to cross-linking agents (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Thus far, 15 distinct genes have been identified to cause the deadly disease (6,(11)(12)(13)(14).…”

“…Thus far, 15 distinct genes have been identified to cause the deadly disease (6,(11)(12)(13)(14). Eight of them are components of the FA core complex (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM) that monoubiquitinates both FANCD2 and FANCI, a key event that initiates interstrand cross-link (ICL) repair (6,8,9,15). Downstream of the FANCD2 and FANCI monoubiquitination are doublestrand break repair proteins (i.e.…”

“…FANCD1/BRCA2, FANCJ/ BRIP1, and FANCN/PALB2, FANCO/RAD51C, and FANCP/SLX4) that are critical to achieving successful ICL repair (6, 11-14, 16, 17). Although a deficiency in each FA gene shows similar clinical and cellular phenotypes, ϳ85% of FA patients present defective FANCA (ϳ60%), FANCC (ϳ15%), or FANCG (ϳ10%) genes, and ϳ15% of them have defects in the other FA genes (8,9,18).…”