Direct DNA Binding Activity of the Fanconi Anemia D2 Protein

Park, Woo-Hyun; Margossian, Steven; Horwitz, Andrew A.; Simons, Amanda M.; D’Andrea, Alan D.; Parvin, Jeffrey D.

doi:10.1074/jbc.m503730200

Cited by 69 publications

(63 citation statements)

References 39 publications

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“…However, it was clear that monoubiquitin- ated FANCD2 did strongly associate with chromatin. Biochemical studies suggest that FANCD2 is able to bind directly to DNA (30). In addition, this protein is phosphorylated by both ATR and ATM DNA checkpoint kinases, which are induced by different kinds of DNA lesions (1,37).…”

Section: Discussionmentioning

confidence: 99%

UBE2T, the Fanconi Anemia Core Complex, and FANCD2 Are Recruited Independently to Chromatin: a Basis for the Regulation of FANCD2 Monoubiquitination

Alpi

Langevin

Mosedale

et al. 2007

Molecular and Cellular Biology

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The Fanconi anemia (FA) nuclear core complex and the E2 ubiquitin-conjugating enzyme UBE2T are required for the S phase and DNA damage-restricted monoubiquitination of FANCD2. This constitutes a key step in the FA tumor suppressor pathway, and much attention has been focused on the regulation at this point. Here, we address the importance of the assembly of the FA core complex and the subcellular localization of UBE2T in the regulation of FANCD2 monoubiquitination. We establish three points. First, the stable assembly of the FA core complex can be dissociated of its ability to function as an E3 ubiquitin ligase. Second, the actual E3 ligase activity is not determined by the assembly of the FA core complex but rather by its DNA damage-induced localization to chromatin. Finally, UBE2T and FANCD2 access this subcellular fraction independently of the FA core complex. FANCD2 monoubiquitination is therefore not regulated by multiprotein complex assembly but by the formation of an active E2/E3 holoenzyme on chromatin.Patients with the rare genetic disorder Fanconi anemia (FA) have a common defect in a DNA damage response pathway that contributes to the maintenance of genome stability (12). The FA pathway consists of a high-molecular-weight nuclear core complex which contains at least 10 subunits

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Section: Discussionmentioning

confidence: 99%

UBE2T, the Fanconi Anemia Core Complex, and FANCD2 Are Recruited Independently to Chromatin: a Basis for the Regulation of FANCD2 Monoubiquitination

Alpi

Langevin

Mosedale

et al. 2007

Molecular and Cellular Biology

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“…Using FANCD2 purified from baculovirus-infected SF9 insect cells, the Parvin group originally determined that full-length FANCD2 binds to dsDNA and Holliday junctions (HJs), quadruplex heteroduplex DNA intermediates that arise during HR. 163 Similarly, the Zhang group purified full-length FANCI and demonstrated that it can bind to multiple DNA substrates, including HJs, dsDNA, ssDNA, and flap structures, without any apparent structural preference. 31 Longerich et al also demonstrated that purified FANCI is capable of binding to dsDNA, ssDNA, and HJs.…”

Section: Fancd2 and Fanci: Dna Bindingmentioning

confidence: 99%

The Fanconi anemia ID2 complex: Dueling saxes at the crossroads

Boisvert

Howlett

2014

Cell Cycle

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“…FANCJ/BRIP1, which is thought to play a role downstream in the FA pathway (23,24,39), is a 5Ј-to-3Ј DNA helicase with substrate specificity towards splayed DNA duplexes (Y-shaped DNA) (14). In support of a role for FA proteins in the processing of DNA structures, a recent study demonstrated that recombinant FANCD2 has direct DNA binding activity in vitro (38). Moreover, Ciccia et al reported that recombinant FANCM is directed to branched DNA structures by a novel FA core complex member, FAAP24 (4).…”

mentioning

confidence: 99%

DNA Structure-Induced Recruitment and Activation of the Fanconi Anemia Pathway Protein FANCD2

Sobeck

Stone

Hoatlin

2007

Molecular and Cellular Biology

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The Fanconi anemia (FA) pathway proteins are thought to be involved in the repair of irregular DNA structures including those encountered by the moving replication fork. However, the nature of the DNA structures that recruit and activate the FA proteins is not known. Because FA proteins function within an extended network of proteins, some of which are still unknown, we recently established cell-free assays in Xenopus laevis egg extracts to deconstruct the FA pathway in a fully replication-competent context. Here we show that the central FA pathway protein, xFANCD2, is monoubiquitinated (xFANCD2-L) rapidly in the presence of linear and branched double-stranded DNA (dsDNA) structures but not single-stranded or Yshaped DNA. xFANCD2-L associates with dsDNA structures in an FA core complex-dependent manner but independently of xATRIP, the regulatory subunit of xATR. Formation of xFANCD2-L is also triggered in response to circular dsDNA, suggesting that dsDNA ends are not required to trigger monoubiquitination of FANCD2. The induction of xFANCD2-L in response to circular dsDNA is replication and checkpoint independent. Our results provide new evidence that the FA pathway discriminates among DNA structures and demonstrate that triggering the FA pathway can be uncoupled from DNA replication and ATRIP-dependent activation.Fanconi anemia (FA) belongs to the group of chromosomal instability syndromes including ataxia telangiectasia, Bloom syndrome, and hereditary breast cancer. FA cells are hypersensitive towards DNA interstrand cross-link (ICL)-inducing agents and have highly elevated spontaneous chromosomal breakage rates, suggesting a role for FA proteins in the DNA damage response. The FA pathway consists of an upstream FA "core complex" containing at least eight proteins (FANCA, -B, -C, -E, -F, -G, -L, and -M) that is required for the DNA damage-induced activation (monoubiquitination) of its downstream target, FANCD2 (9,12,13,18,27,37). Accumulating evidence supports a role for the FA pathway in DNA doublestrand break (DSB) repair via homologous recombination (HR). Indeed, FA cells are defective in the repair of ICLinduced DNA DSBs mediated by HR (44). Activated FANCD2 interacts with major components of HR repair, such as BRCA1 (breast cancer-associated protein 1), Rad51, and the downstream FA protein BRCA2/FANCD1 (8,12,17,22,47,49); moreover, the BRCA2 interactor PALB2 was recently identified as a Fanconi protein, FANCN (42,43,50). In addition, involvement of the FA proteins in DNA DSB repair via single-strand annealing and nonhomologous end joining has been suggested (10,11,26,36). The recently identified FANCM and FANCJ proteins indicate a direct involvement of FA proteins at sites of DNA repair: FANCM is an FA core complex member (30,31,34) homologous to the archaeal protein Hef (helicase-associated endonuclease for fork-structured DNA), which resolves stalled replication forks (20). FANCJ/BRIP1, which is thought to play a role downstream in the FA pathway (23,24,39), is a 5Ј-to-3Ј DNA helicase with substrate spe...

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Direct DNA Binding Activity of the Fanconi Anemia D2 Protein

Cited by 69 publications

References 39 publications

UBE2T, the Fanconi Anemia Core Complex, and FANCD2 Are Recruited Independently to Chromatin: a Basis for the Regulation of FANCD2 Monoubiquitination

UBE2T, the Fanconi Anemia Core Complex, and FANCD2 Are Recruited Independently to Chromatin: a Basis for the Regulation of FANCD2 Monoubiquitination

The Fanconi anemia ID2 complex: Dueling saxes at the crossroads

DNA Structure-Induced Recruitment and Activation of the Fanconi Anemia Pathway Protein FANCD2

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