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The Fanconi anemia protein FANCM is controlled by FANCD2 and the ATR/ATM pathways.

ABSTRACT: Genomic stability requires a functional Fanconi anemia (FA) pathway composed of an upstream "core complex" (FA proteins A/B/C/E/F/G/L/M) that mediates monoubiquitination of the downstream targets FANCD2 and FANCI. Unique among FA core complex members, FANCM has processing activities toward replication-associated DNA structures, suggesting a vital role for FANCM during replication. Using Xenopus egg extracts, we analyzed the functions of FANCM in replication and the DNA damage response. xFANCM binds chromatin in a replication-dependent manner and is phosphorylated in response to DNA damage structures. Chromatin binding and DNA damage-induced phosphorylation of xFANCM are mediated in part by the downstream FA pathway protein FANCD2. Moreover, phosphorylation and chromatin recruitment of FANCM is regulated by two mayor players in the DNA damage response: the cell cycle checkpoint kinases ATR and ATM. Our results indicate that functions of FANCM are controlled by FA- and non-FA pathways in the DNA damage response.

SUBMITTER: Sobeck A

PROVIDER: S-EPMC2757957 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Fanconi anemia protein FANCD2 inhibits TRF1 polyADP-ribosylation through tankyrase1-dependent manner.

Project description:BackgroundFanconi anemia (FA) is a rare autosomal recessive syndrome characterized by developmental abnormalities, progressive bone marrow failure, and predisposition to cancer. The key FA protein FANCD2 crosstalks with members of DNA damage and repair pathways that also play a role at telomeres. Therefore, we investigated whether FANCD2 has a similar involvement at telomeres.ResultsWe reveal that FANCD2 may perform a novel function separate to the FANCD2/BRCA pathway. This function includes FANCD2 interaction with one of the telomere components, the PARP family member tankyrase-1. Moreover, FANCD2 inhibits tankyrase-1 activity in vitro. In turn, FANCD2 deficiency increases the polyADP-ribosylation of telomere binding factor TRF1.ConclusionsFANCD2 binding and inhibiting tankyrase-1PARsylation at telomeres may provide an additional step within the FA pathway for the regulation of genomic integrity.

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Direct inhibition of TNF-α promoter activity by Fanconi anemia protein FANCD2.

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Remodeling of Interstrand Crosslink Proximal Replisomes Is Dependent on ATR, FANCM, and FANCD2.

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Defective FANCI binding by a fanconi anemia-related FANCD2 mutant.

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MHF1-MHF2, a histone-fold-containing protein complex, participates in the Fanconi anemia pathway via FANCM.

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Defining the molecular interface that connects the Fanconi anemia protein FANCM to the Bloom syndrome dissolvasome.

Project description:The RMI subcomplex (RMI1/RMI2) functions with the BLM helicase and topoisomerase IIIα in a complex called the "dissolvasome," which separates double-Holliday junction DNA structures that can arise during DNA repair. This activity suppresses potentially harmful sister chromatid exchange (SCE) events in wild-type cells but not in cells derived from Bloom syndrome patients with inactivating BLM mutations. The RMI subcomplex also associates with FANCM, a component of the Fanconi anemia (FA) core complex that is important for repair of stalled DNA replication forks. The RMI/FANCM interface appears to help coordinate dissolvasome and FA core complex activities, but its precise role remains poorly understood. Here, we define the structure of the RMI/FANCM interface and investigate its roles in coordinating cellular DNA-repair activities. The X-ray crystal structure of the RMI core complex bound to a well-conserved peptide from FANCM shows that FANCM binds to both RMI proteins through a hydrophobic "knobs-into-holes" packing arrangement. The RMI/FANCM interface is shown to be critical for interaction between the components of the dissolvasome and the FA core complex. FANCM variants that substitute alanine for key interface residues strongly destabilize the complex in solution and lead to increased SCE levels in cells that are similar to those observed in blm- or fancm-deficient cells. This study provides a molecular view of the RMI/FANCM complex and highlights a key interface utilized in coordinating the activities of two critical eukaryotic DNA-damage repair machines.

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Cooperation of the ATM and Fanconi Anemia/BRCA Pathways in Double-Strand Break End Resection.

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Architecture and DNA recognition elements of the Fanconi anemia FANCM-FAAP24 complex.

Project description:Fanconi anemia (FA) is a disorder associated with a failure in DNA repair. FANCM (defective in FA complementation group M) and its partner FAAP24 target other FA proteins to sites of DNA damage. FANCM-FAAP24 is related to XPF/MUS81 endonucleases but lacks endonucleolytic activity. We report a structure of an FANCM C-terminal fragment (FANCMCTD) bound to FAAP24 and DNA. This S-shaped structure reveals the FANCM (HhH)2 domain is buried, whereas the FAAP24 (HhH)2 domain engages DNA. We identify a second DNA contact and a metal center within the FANCM pseudo-nuclease domain and demonstrate that mutations in either region impair double-stranded DNA binding in vitro and FANCM-FAAP24 function in vivo. We show the FANCM translocase domain lies in proximity to FANCMCTD by electron microscopy and that binding fork DNA structures stimulate its ATPase activity. This suggests a tracking model for FANCM-FAAP24 until an encounter with a stalled replication fork triggers ATPase-mediated fork remodeling.

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Epithelial cancer in Fanconi anemia complementation group D2 (Fancd2) knockout mice.

Project description:Fanconi anemia (FA) is a genetic disorder characterized by hypersensitivity to DNA damage, bone marrow failure, congenital defects, and cancer. To further investigate the in vivo function of the FA pathway, mice with a targeted deletion in the distally acting FA gene Fancd2 were created. Similar to human FA patients and other FA mouse models, Fancd2 mutant mice exhibited cellular sensitivity to DNA interstrand cross-links and germ cell loss. In addition, chromosome mispairing was seen in male meiosis. However, Fancd2 mutant mice also displayed phenotypes not observed in other mice with disruptions of proximal FA genes. These include microphthalmia, perinatal lethality, and epithelial cancers, similar to mice with Brca2/Fancd1 hypomorphic mutations. These additional phenotypes were not caused by defects in the ATM-mediated S-phase checkpoint, which was intact in primary Fancd2 mutant fibroblasts. The phenotypic overlap between Fancd2-null and Brca2/Fancd1 hypomorphic mice is consistent with a common function for both proteins in the same pathway, regulating genomic stability.

| S-EPMC196256 | biostudies-literature

Fanconi anemia protein FANCD2 is activated by AICAR, a modulator of AMPK and cellular energy metabolism.

Project description:FANCD2 is a pivotal molecule in the pathogenesis of Fanconi anemia (FA), an autosomal recessive human syndrome with diverse clinical phenotypes, including cancer predisposition, short stature, and hematological abnormalities. In our previous study, we detected the functional association of FANC proteins, whose mutations are responsible for the onset of FA, with AMPK in response to DNA interstrand crosslinking lesions. Because AMPK is well known as a critical sensing molecule for cellular energy levels, we checked whether FANCD2 activation occurs after treatments affecting AMPK and/or cellular energy status. Among the treatments tested, AMPK-activating 5-aminoimidazole-4-carboxamide-ribonucleoside (AICAR) induced monoubiquitination and nuclear foci formation of FANCD2, which are biomarkers of FANCD2 activation. FANCD2 activation was abolished by treatments with Compound C, an AMPK inhibitor, or after AMPK?1 knockdown, substantiating the involvement of AMPK in AICAR-induced FANCD2 activation. Similarly, FANCA protein, which is a component of the FA core complex monoubiquitinating FANCD2, was required for this event. Furthermore, FANCD2 repression enhanced cell death upon AICAR treatments in transformed fibroblasts and cell cycle arrest in the renal cell carcinoma cell line Caki-1. Overall, this study showed FANCD2 involvement in response to AICAR, a chemical modulating cellular energy metabolism.

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