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

Yuan, Fenghua; Qian, Liangyue; Zhao, Xuezhi; Liu, Jessie Y.; Song, Limin; D’Urso, Gennaro; Jain, Chaitanya; Zhang, Yanbin

doi:10.1074/jbc.m111.315366

Cited by 26 publications

(44 citation statements)

References 61 publications

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“…How the A-G-20 module promote the chromatin E3 ligase activity remains unclear. FANCA has been shown to exhibit DNA binding affinity in vitro (Yuan et al, 2012). FAAP20 can bind to ubiquitinated forms of H2A (Yan et al, 2012), although the weak phenotypes of FAAP20 mutant suggest a secondary role for FAAP20 in chromatin association of the core complex.…”

Section: Discussionmentioning

confidence: 99%

Modularized Functions of the Fanconi Anemia Core Complex

et al. 2014

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SUMMARY The Fanconi Anemia (FA) core complex provides the essential E3 ligase function for the FA pathway activation through the spatially defined FANCD2 ubiquitination. Of the seven FA gene products forming the core complex, FANCL possesses a RING domain with demonstrated E3 ligase activity. The other six components have no clearly defined roles. Through epistatic analyses, we identified three functional modules in the FA core complex: a catalytic module consisting of FANCL, FANCB, and FAAP100 is absolutely required for the E3 ligase function; the FANCA-FANCG-FAAP20 module and the FANCC-FANCE-FANCF module provide non-redundant and ancillary functions supporting the chromatin and DNA damage association of the catalytic module. Disruption of the catalytic module renders total loss of the core complex function whereas loss of any ancillary module component does not. Our work revealed the roles of several FA gene products with previously undefined functions and a modularized assembly of the FA core complex.

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Section: Discussionmentioning

confidence: 99%

Modularized Functions of the Fanconi Anemia Core Complex

et al. 2014

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“…The A-G module may also function in chromatin targeting of the complex suggested by data showing intrinsic DNA binding of FANCA (Yuan et al., 2012) and the association of FANCA with FAAP20, a ubiquitin-binding-zinc-finger-containing protein that binds ubiquitin chains assembled by RNF8 and promotes chromatin targeting of the core complex and FANCD2 in vivo (Ali et al., 2012; Leung et al., 2012; Yan et al., 2012). …”

Section: Discussionmentioning

confidence: 99%

The Genetic and Biochemical Basis of FANCD2 Monoubiquitination

et al. 2014

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SummaryFanconi anaemia (FA) is a cancer predisposition syndrome characterized by cellular sensitivity to DNA interstrand crosslinkers. The molecular defect in FA is an impaired DNA repair pathway. The critical event in activating this pathway is monoubiquitination of FANCD2. In vivo, a multisubunit FA core complex catalyzes this step, but its mechanism is unclear. Here, we report purification of a native avian FA core complex and biochemical reconstitution of FANCD2 monoubiquitination. This demonstrates that the catalytic FANCL E3 ligase subunit must be embedded within the complex for maximal activity and site specificity. We genetically and biochemically define a minimal subcomplex comprising just three proteins (FANCB, FANCL, and FAAP100) that functions as the monoubiquitination module. Residual FANCD2 monoubiquitination activity is retained in cells defective for other FA core complex subunits. This work describes the in vitro reconstitution and characterization of this multisubunit monoubiquitin E3 ligase, providing key insight into the conserved FA DNA repair pathway.

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“…It is localized to chromatin in a replication-dependent manner [44–46]. Xenopus egg extracts immune-depletion study shows that FANCA is directly involved in maintenance of replication forks [47,48].…”

Section: Introductionmentioning

confidence: 99%

Human Fanconi Anemia Complementation Group A Protein Stimulates the 5’ Flap Endonuclease Activity of FEN1

et al. 2013

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In eukaryotic cells, Flap endonuclease 1 (FEN1) is a major structure-specific endonuclease that processes 5’ flapped structures during maturation of lagging strand DNA synthesis, long patch base excision repair, and rescue of stalled replication forks. Here we report that fanconi anemia complementation group A protein (FANCA), a protein that recognizes 5’ flap structures and is involved in DNA repair and maintenance of replication forks, constantly stimulates FEN1-mediated incision of both DNA and RNA flaps. Kinetic analyses indicate that FANCA stimulates FEN1 by increasing the turnover rate of FEN1 and altering its substrate affinity. More importantly, six pathogenic FANCA mutants are significantly less efficient than the wild-type at stimulating FEN1 endonuclease activity, implicating that regulation of FEN1 by FANCA contributes to the maintenance of genomic stability.

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

Cited by 26 publications

References 61 publications

Modularized Functions of the Fanconi Anemia Core Complex

Modularized Functions of the Fanconi Anemia Core Complex

The Genetic and Biochemical Basis of FANCD2 Monoubiquitination

Human Fanconi Anemia Complementation Group A Protein Stimulates the 5’ Flap Endonuclease Activity of FEN1

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