The Fanconi Family Adds a Fraternal Twin

Grompe, Markus; Vrugt, Henri van de

doi:10.1016/j.devcel.2007.04.008

Cited by 29 publications

(29 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although only FANCL has intrinsic E3 ligase activity, depletion of any component of the FA core complex compromises FANCI/FAND2 monoubiquitination (1,8,28). Thus, monoubiquitination of FANCD2 has been used as a surrogate marker for the integrity or the activation of the FA pathway.…”

Section: Faap20 Contains An Evolutionarily Conserved Rad18-like Ubiqumentioning

confidence: 99%

Fanconi anemia (FA) binding protein FAAP20 stabilizes FA complementation group A (FANCA) and participates in interstrand cross-link repair

Leung

Wang

Fong

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The Fanconi anemia (FA) pathway participates in interstrand crosslink (ICL) repair and the maintenance of genomic stability. The FA core complex consists of eight FA proteins and two Fanconi anemiaassociated proteins (FAAP24 and FAAP100). The FA core complex has ubiquitin ligase activity responsible for monoubiquitination of the FANCI-FANCD2 (ID) complex, which in turn initiates a cascade of biochemical events that allow processing and removal of crosslinked DNA and thereby promotes cell survival following DNA damage. Here, we report the identification of a unique component of the FA core complex, namely, FAAP20, which contains a RAD18-like ubiquitin-binding zinc-finger domain. Our data suggest that FAAP20 promotes the functional integrity of the FA core complex via its direct interaction with the FA gene product, FANCA. Indeed, somatic knockout cells devoid of FAAP20 displayed the hallmarks of FA cells, including hypersensitivity to DNA cross-linking agents, chromosome aberrations, and reduced FANCD2 monoubiquitination. Taking these data together, our study indicates that FAAP20 is an important player involved in the FA pathway.is a rare recessive genetic disorder characterized by bone marrow failure, congenital developmental defects, and cancer predisposition (1-4). Cellular features of FA include chromosomal instability and hypersensitivity to crosslinking agents (5). Fifteen FA complementation genes have been identified so far. These genes form several complexes to orchestrate interstrand cross-linking (ICL) repair. The FA core complex is composed of eight of the FA gene products (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM), in addition to FAAP24 and FAAP100 (6, 7), and acts as an E3 ligase to ubiquitinate FANCI/FANCD2 (I/D2) complex (8-11). The monoubiquitinated FANCI/FANCD2 complex interacts with Fanconi anemia-associated nuclease 1 (FAN1), which has exonuclease and endonuclease activity that may unhook the ICL, facilitate translesion synthesis, and promote downstream homologous recombination (HR) repair (12-15).Besides the FA core complex and FANCI/FANCD2, there are several other FA proteins that likely act downstream of FANCI/ FANCD2 and participate in HR repair. These proteins include BRCA2 (FANCD1) and PALB2 (FANCN), both of which are essential for HR repair (16-18). Another downstream FA protein, BACH1 (FANCJ), is also a bona fide double-strand break repair factor (19). BRCA2/FANCD1, PALB2/FANCN, and BACH1/FANCJ are all recruited to ICL sites (20), indicating that they are directly involved in ICL repair. More recently, mutations in two other genes, RAD51C/FANCO and SLX4/FANCP, were identified in patients with FA phenotypes (21-23), suggesting that there may be additional FA genes responsible for this disease.Not all FA proteins function in a linear pathway involved in ICL repair. Many of the downstream FA proteins are involved in HR repair and associated with breast cancer susceptibility (16-19, 24, 25). These proteins all have functions besides ICL repair. More recently, another DN...

show abstract

Section: Faap20 Contains An Evolutionarily Conserved Rad18-like Ubiqumentioning

confidence: 99%

Fanconi anemia (FA) binding protein FAAP20 stabilizes FA complementation group A (FANCA) and participates in interstrand cross-link repair

Leung

Wang

Fong

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…The extremely high incidence of cancer in FA patients indicates the essential nature of this pathway in tumor suppression (7,9,11,12); however, the role of this pathway in the development and progression of non-FA human cancer has not been adequately studied. Both DNA damage and DNA replication can activate this pathway, leading to monoubiquitination of FA complementation group D2 protein (FANCD2) (13) and its paralog FANCI (14,15) through an E3 ubiquitin ligase complex comprising 8 known FA proteins (9), 2 FA-associated proteins (16,17), and unknown proteins, with FANCL serving as a catalytic subunit (18,19). The monoubiquitinated FANCD2 (13) and FANCI (14,15) then function in concert with proteins such as FANCD1/BRCA2 (4), FANCN/PALB2 (10,20), FANCJ/BRIP1/ BACH1 (5,6,21), and others to repair damaged DNA.…”

Section: Introductionmentioning

confidence: 99%

“…Both DNA damage and DNA replication can activate this pathway, leading to monoubiquitination of FA complementation group D2 protein (FANCD2) (13) and its paralog FANCI (14,15) through an E3 ubiquitin ligase complex comprising 8 known FA proteins (9), 2 FA-associated proteins (16,17), and unknown proteins, with FANCL serving as a catalytic subunit (18,19). The monoubiquitinated FANCD2 (13) and FANCI (14,15) then function in concert with proteins such as FANCD1/BRCA2 (4), FANCN/PALB2 (10,20), FANCJ/BRIP1/ BACH1 (5,6,21), and others to repair damaged DNA. Moreover, FANCD2 and/or FANCI monoubiquitination appears to be a measure of the activation of the FA-BRCA pathway (11,14).…”

Section: Introductionmentioning

confidence: 99%

“…The monoubiquitinated FANCD2 (13) and FANCI (14,15) then function in concert with proteins such as FANCD1/BRCA2 (4), FANCN/PALB2 (10,20), FANCJ/BRIP1/ BACH1 (5,6,21), and others to repair damaged DNA. Moreover, FANCD2 and/or FANCI monoubiquitination appears to be a measure of the activation of the FA-BRCA pathway (11,14). With discoveries that 2 FA proteins FANCD1 (4) and FANCN (10,20) are BRCA2 and PALB2, respectively, and that 2 other FA proteins FANCJ (5,6,21) and FANCM (22) are a DNA helicase and translocase, respectively, FA has emerged as a unique genetic model to our knowledge to study mechanisms underlying genomic instability.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

FAVL elevation in human tumors disrupts Fanconi anemia pathway signaling and promotes genomic instability and tumor growth

et al. 2010

View full text Add to dashboard Cite

Fanconi anemia (FA) is a rare human genetic disease caused by mutations in any one of 13 known genes that encode proteins functioning in one common signaling pathway, the FA pathway, or in unknown genes. One characteristic of FA is an extremely high incidence of cancer, indicating the importance of the FA pathway in tumor suppression. However, the role of this pathway in the development and progression of human cancers in individuals who do not have FA has not been clearly determined. Here, we report that elevated expression of what we believe to be a novel splice variant of FA complementation group L (FANCL), which we identified and named FAVL, can impair the FA pathway in non-FA human tumor cells and act as a tumor promoting factor. FAVL expression was elevated in half of the human carcinoma cell lines and carcinoma tissue samples tested. Expression of FAVL resulted in decreased FANCL expression by sequestering FANCL to the cytoplasm and enhancing its degradation. Importantly, this impairment of the FA pathway by FAVL elevation provided human cancer cells with a growth advantage, caused chromosomal instability in vitro, and promoted tumor development in a xenograft mouse model. These data indicate that FAVL impairment of the FA pathway likely contributes to the development of non-FA human cancers and therefore add a challenging layer of complexity to the pathogenesis of human cancer. We further believe that these data will prove useful for developing additional tools for fighting human cancer.

show abstract

“…Its main function is to monoubiquitylate FANCD2 and FANCI, that is group II, in response to DNA damages induced by mitomycin C, ionizing radiation, ultraviolet, or during the S phase of the cell cycle. 12 Then, FANCD2 and FANCI, also known as FA "ID" complex, are translocated to DNA-repair subnuclear foci where they colocalize with FA proteins of the third group FANCD1 (or BRCA2), FANCJ (or BRIP1) and FANCN (or PALB2), forming stable complexes with other proteins involved in HR at sites of DNA damages such as BRCA1 13 and RAD51. 14 At the collapsed replication fork, a DSB is generated and FA proteins recruits HR to repair by keeping the broken strands in close proximity.…”

Section: Introductionmentioning

confidence: 99%

Role of Fanconi DNA repair pathway in neural stem cell homeostasis

Sii-Felice¹,

Barroca²,

Étienne³

et al. 2008

Cell Cycle

View full text Add to dashboard Cite

Defects in DNA repair pathways have been involved in collapse of early neurogenesis leading to brain development abnormalities and embryonic lethality. However, consequences of DNA repair defects in adult neural stem and progenitor cells and their potential contribution in ageing phenotype are poorly understood. The Fanconi anaemia (FA) pathway, which functions primarily as a DNA damage response system, has been examined in neural stem and progenitor cells during developmental and adult neurogenesis. We have shown that loss of fanca and fancg specifically provokes neural progenitor apoptosis during forebrain development, related to DNA repair defects, which persists in adulthood leading to depletion of the neural stem cell pool with ageing. In addition, neural stem cells from FA mice had a reduced capacity to self-renew in vitro. Here, we expand upon our recent work and give further data examining possible implication of oxidative stress. Therefore, FA phenotype might be interpreted as a premature ageing of stem cells, DNA damages being among the driving forces of ageing.

show abstract

The Fanconi Family Adds a Fraternal Twin

Cited by 29 publications

References 11 publications

Fanconi anemia (FA) binding protein FAAP20 stabilizes FA complementation group A (FANCA) and participates in interstrand cross-link repair

Fanconi anemia (FA) binding protein FAAP20 stabilizes FA complementation group A (FANCA) and participates in interstrand cross-link repair

FAVL elevation in human tumors disrupts Fanconi anemia pathway signaling and promotes genomic instability and tumor growth

Role of Fanconi DNA repair pathway in neural stem cell homeostasis

Contact Info

Product

Resources

About