How the Fanconi Anemia Pathway Guards the Genome

Moldovan, George‐Lucian; D’Andrea, Alan D.

doi:10.1146/annurev-genet-102108-134222

Cited by 532 publications

(608 citation statements)

References 172 publications

(304 reference statements)

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“…1 At the cellular level, FA patients have defective DNA repair, 6 and therefore in these patients we first assessed the number of apoptotic epithelial cells in the skin and gut biopsies performed before HSCT for diagnostic purposes. The fact that, in both the skin and gut biopsies, apoptotic cell numbers were small in nontransplanted FA patients implies that the high level of epithelial apoptosis observed in FA patients with aGVHD was not due to damage that existed before HSCT.…”

Section: Discussionmentioning

confidence: 99%

“…As FA patients also have DNA hypersensitivity to DNA-crosslinking agents, 6 we then set out to assess the role of the conditioning regimen on the epithelial cell apoptosis in these patients. The conditioning regimen, particularly radiotherapy, could have a role in the epithelial cell apoptosis, as TP53-induced apoptosis is involved in radiation toxicity in normal tissues.…”

Section: Discussionmentioning

confidence: 99%

“…5 At the cellular level, the hallmarks of FA are hypersensitivity to DNA-cross-linking agents and defective DNA repair. 6 Unrepaired DNA damage can further activate p53-dependent 7 and p53-independent 8 signaling pathways of apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Increased apoptosis is linked to severe acute GVHD in patients with Fanconi anemia

Wang

Romero

Ratajczak

et al. 2012

Bone Marrow Transplant

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Fanconi anemia (FA) patients have an increased risk of acute GVHD (aGVHD) after hematopoietic SCT, with hypersensitivity to DNAcross-linking agents and defective DNA repair. MicroRNA-34 and p53 can induce apoptosis after DNA damage.Here we assessed epithelial cell apoptosis, and studied TP53 and miR-34a expression in the skin and gut biopsies in five non-transplanted FA patients, in 20 FA patients with aGVHD and in 25 acquired aplastic anemia patients (AA). Epithelial apoptosis was higher in FA than in acquired AA patients in both the skin and gut biopsies, though they had a similar preparative regimen. Further study on gut biopsies in FA patients showed that this deleterious effect was not linked to TP53 gene overexpression. As, among p53-independent signaling pathways of apoptosis, the microRNA-34 family mimics p53 apoptotic effects in response to DNA damage, we studied miR-34a expression in the same series of FA patients' gut biopsies. MiR-34a expression level was higher in severe aGVHD compared with non-aGVHD subjects or non-transplanted patients, and significantly related to apoptotic cell numbers across the three groups of FA patients. Thus, in FA patients, increased apoptosis occurs in target epithelial cells of severe aGVHD, and this deleterious effect is linked to overexpression of miR-34a but not TP53.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Increased apoptosis is linked to severe acute GVHD in patients with Fanconi anemia

Wang

Romero

Ratajczak

et al. 2012

Bone Marrow Transplant

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“…1,2 Although deficiency in DNA cross-link repair renders all FA cells susceptible to cross-linking agents, bone marrow is the most affected organ system. Mutations in any of the different FA genes almost universally lead to bone marrow failure, which is the primary cause of mortality in FA.…”

Section: Fancd1/brca2 Fancd2 Fance Fancf Fancg/xrcc9 Fanci Fancmentioning

confidence: 99%

Fancd2 −/− mice have hematopoietic defects that can be partially corrected by resveratrol

Zhang

Marquez-Loza

Eaton

et al. 2010

Blood

106

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Progressive bone marrow failure is a major cause of morbidity and mortality in human Fanconi Anemia patients. In an effort to develop a Fanconi Anemia murine model to study bone marrow failure, we found that Fancd2 ؊/؊ mice have readily measurable hematopoietic defects. Fancd2 deficiency was associated with a significant decline in the size of the c-Kit ؉ Sca-1 ؉ Lineage ؊ (KSL) pool and reduced stem cell repopulation and spleen colony-forming capacity. Fancd2 ؊/؊ KSL cells showed an abnormal cell cycle status and loss of quiescence. In addition, the supportive function of the marrow microenvironment was compromised in Fancd2 ؊/؊ mice. Treatment with Sirt1-mimetic and the antioxidant drug, resveratrol, maintained Fancd2 ؊/؊ KSL cells in quiescence, improved the marrow microenvironment, partially corrected the abnormal cell cycle status, and significantly improved the spleen colony-forming capacity of Fancd2 ؊/؊ bone marrow cells. We conclude that Fancd2 ؊/؊ mice have readily quantifiable hematopoietic defects, and that this model is well suited for pharmacologic screening studies. IntroductionFanconi anemia (FA) is a rare, autosomal, recessive genetic disorder associated with severe birth defects, cancer predisposition, and bone marrow failure. Thirteen causative genes (FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG/XRCC9, FANCI, FANCL/PHF9/Pog, FANCJ/BRIP1/BACH1, FANCM/Hef, and FANCN/ PALB2) have been identified and cloned to date, and the encoded proteins are believed to work together in a common DNA damageresponse pathway to maintain genomic integrity and protect the genome from DNA damage induced by cross-linking agents. 1,2 Although deficiency in DNA cross-link repair renders all FA cells susceptible to cross-linking agents, bone marrow is the most affected organ system. Mutations in any of the different FA genes almost universally lead to bone marrow failure, which is the primary cause of mortality in FA. 3 The pathogenesis of bone marrow failure in FA remains elusive. Mutations in several genes involved in DNA damage repair, including Atr, XPD, and Ercc1, caused either hematopoietic stem cell (HSC) loss or impaired HSC function under conditions of stress. [4][5][6] These studies suggest that the maintenance of genome integrity is critical for HSC survival and function. However, the extent to which genotoxicity, resulting from impaired DNA damage repair, contributes to bone marrow failure in FA is unclear. 7 Other pathways associated with hematopoietic failure, such as altered cytokine signaling, may also contribute to FA pathogenesis. 8,9 For example, levels of proapoptotic cytokines tumor necrosis factor-␣ (TNF-␣) and interferon-␥ (IFN-␥) are elevated in FA lymphocytes, bone marrow cells, and FA patient serum samples. 10-12 FA bone marrow cells (at least of the C complementation group) are also hypersensitive to these cytokines and undergo apoptosis when exposed to even low levels of them. [13][14][15] To better understand FA, multiple murine knockout models, includingand Fancl Ϫ/Ϫ m...

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“…FANCL contains a RING finger domain and is the catalytic subunit of the FA core complex. Monoubiquitylation induces ID2 translocation to chromatin foci containing ICL lesions (Moldovan & D'Andrea 2009). FAN1 (FANCD2/FANCI‐associated nuclease 1) is then recruited to monoubiquitylated ID2 via its UBZ4‐type ubiquitin binding domain (UBD) and cleaves the DNA, thereby initiating ICL repair.…”

Section: Regulation Of Dna Damage Repair and Dna Replication By Monoumentioning

confidence: 99%

Protein monoubiquitylation: targets and diverse functions

Nakagawa

Nakayama

2015

Genes to Cells

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Ubiquitin is a 76‐amino acid protein whose conjugation to protein targets is a form of post‐translational modification. Protein ubiquitylation is characterized by the covalent attachment of the COOH‐terminal carboxyl group of ubiquitin to an amino group of the substrate protein. Given that the NH2‐terminal amino group is usually masked, internal lysine residues are most often targeted for ubiquitylation. Polyubiquitylation refers to the formation of a polyubiquitin chain on the substrate as a result of the ubiquitylation of conjugated ubiquitin. The structures of such polyubiquitin chains depend on the specific lysine residues of ubiquitin targeted for ubiquitylation. Most of the polyubiquitin chains other than those linked via lysine‐63 and methionine‐1 of ubiquitin are recognized by the proteasome and serve as a trigger for substrate degradation. In contrast, polyubiquitin chains linked via lysine‐63 and methionine‐1 serve as a binding platform for proteins that function in immune signal transduction or DNA repair. With the exception of a few targets such as histones, the functions of protein monoubiquitylation have remained less clear. However, recent proteomics analysis has shown that monoubiquitylation occurs more frequently than polyubiquitylation, and studies are beginning to provide insight into its biologically important functions. Here, we summarize recent findings on protein monoubiquitylation to provide an overview of the targets and molecular functions of this modification.

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How the Fanconi Anemia Pathway Guards the Genome

Cited by 532 publications

References 172 publications

Increased apoptosis is linked to severe acute GVHD in patients with Fanconi anemia

Increased apoptosis is linked to severe acute GVHD in patients with Fanconi anemia

Fancd2 −/− mice have hematopoietic defects that can be partially corrected by resveratrol

Protein monoubiquitylation: targets and diverse functions

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