Cells derived from Fanconi anemia (FA) patients are characterized by hypersensitivity to DNA interstrand crosslinks (ICLs), suggesting that FA genes play a role in ICL repair. Fanconi anemia core complex (including A, B, C, E, F, G, L, FAAP20, and FAAP100) activates the Fanconi pathway by providing the essential E3 ligase activity for FANCD2 mono-ubiquitination. Previous studies suggested the existence of three protein-protein interaction groups. However, the functions of most FA core complex protein are still limited to their presence in the complex. How the spatially-defined FANCD2 ubiquitination is accomplished by the core complex remains unknown.
To elucidate the roles of FA core complex proteins in ICL response, especially their contribution to FANCD2 ubiquitination, we established isogenic knockout mutants deficient in FA core genes and determined the loss-of-function effects on the activation of FA pathway and on cellular survival against ICLs. Our results suggest three potential functional modules in the FA core complex: FANCB-FANCL-FAAP100 (B-L-100), FANCA-FANCG-FAAP20 (A-G-20), and FANC-FANCE-FANCF (C-E-F). We showed that the B-L-100 sub complex is the catalytic module absolutely required for the E3 ligase function of FA core complex. The A-G-20 module anchors the catalytic module to the chromatin. The C-E-F module acts as a loading factor of the core complex through FANCM. Our work revealed that the FA core complex is assembled with functional modules and carries out the spatially-defined FANCD2 monoubiquitination reaction to ensure that nucleases for DNA damage processing are enriched at the site of lesion. The deviate functions of different FA core complementation groups imply differential disease biology related to prognosis and treatment.
","abstract_html":"<p>Cells derived from Fanconi anemia (FA) patients are characterized by hypersensitivity to DNA interstrand crosslinks (ICLs), suggesting that FA genes play a role in ICL repair. Fanconi anemia core complex (including A, B, C, E, F, G, L, FAAP20, and FAAP100) activates the Fanconi pathway by providing the essential E3 ligase activity for FANCD2 mono-ubiquitination. Previous studies suggested the existence of three protein-protein interaction groups. However, the functions of most FA core complex protein are still limited to their presence in the complex. How the spatially-defined FANCD2 ubiquitination is accomplished by the core complex remains unknown.</p> <p>To elucidate the roles of FA core complex proteins in ICL response, especially their contribution to FANCD2 ubiquitination, we established isogenic knockout mutants deficient in FA core genes and determined the loss-of-function effects on the activation of FA pathway and on cellular survival against ICLs. Our results suggest three potential functional modules in the FA core complex: FANCB-FANCL-FAAP100 (B-L-100), FANCA-FANCG-FAAP20 (A-G-20), and FANC-FANCE-FANCF (C-E-F). We showed that the B-L-100 sub complex is the catalytic module absolutely required for the E3 ligase function of FA core complex. The A-G-20 module anchors the catalytic module to the chromatin. The C-E-F module acts as a loading factor of the core complex through FANCM. Our work revealed that the FA core complex is assembled with functional modules and carries out the spatially-defined FANCD2 monoubiquitination reaction to ensure that nucleases for DNA damage processing are enriched at the site of lesion. The deviate functions of different FA core complementation groups imply differential disease biology related to prognosis and treatment.</p>","abstract_has_math":false,"creators":["Huang, Yaling"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation (PhD)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Lei Li","Junjie Chen","Randy J Legerski"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2014,"date_issued":"2014-05-01T07:00:00Z","date_published":"2014-05-01T07:00:00Z","updated_at":"2026-07-24T05:49:54Z","subjects":["Fanconi anemia","interstrand crosslink","DNA repair","Cancer Biology","Medical Genetics","Molecular Genetics"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/429","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Lei Li","Junjie Chen","Randy J Legerski"]},{"key":"dc:creator","label":"Author","values":["Huang, Yaling"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2014-10-01T07:00:00Z"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation (PhD)"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Fanconi anemia","interstrand crosslink","DNA repair","Cancer Biology","Medical Genetics","Molecular Genetics"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/429"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Cells derived from Fanconi anemia (FA) patients are characterized by hypersensitivity to DNA interstrand crosslinks (ICLs), suggesting that FA genes play a role in ICL repair. Fanconi anemia core complex (including A, B, C, E, F, G, L, FAAP20, and FAAP100) activates the Fanconi pathway by providing the essential E3 ligase activity for FANCD2 mono-ubiquitination. Previous studies suggested the existence of three protein-protein interaction groups. However, the functions of most FA core complex protein are still limited to their presence in the complex. How the spatially-defined FANCD2 ubiquitination is accomplished by the core complex remains unknown.
To elucidate the roles of FA core complex proteins in ICL response, especially their contribution to FANCD2 ubiquitination, we established isogenic knockout mutants deficient in FA core genes and determined the loss-of-function effects on the activation of FA pathway and on cellular survival against ICLs. Our results suggest three potential functional modules in the FA core complex: FANCB-FANCL-FAAP100 (B-L-100), FANCA-FANCG-FAAP20 (A-G-20), and FANC-FANCE-FANCF (C-E-F). We showed that the B-L-100 sub complex is the catalytic module absolutely required for the E3 ligase function of FA core complex. The A-G-20 module anchors the catalytic module to the chromatin. The C-E-F module acts as a loading factor of the core complex through FANCM. Our work revealed that the FA core complex is assembled with functional modules and carries out the spatially-defined FANCD2 monoubiquitination reaction to ensure that nucleases for DNA damage processing are enriched at the site of lesion. The deviate functions of different FA core complementation groups imply differential disease biology related to prognosis and treatment.
"]},{"key":"dc:title","label":"Title","values":["Modulated Functions of The Fanconi Anemia Core Complex"]}]}],"canonical_facts":{"dc:contributor":["Lei Li","Junjie Chen","Randy J Legerski"],"dc:creator":["Huang, Yaling"],"dc:date.available":["2014-10-01T07:00:00Z"],"dc:description.abstract":["Cells derived from Fanconi anemia (FA) patients are characterized by hypersensitivity to DNA interstrand crosslinks (ICLs), suggesting that FA genes play a role in ICL repair. Fanconi anemia core complex (including A, B, C, E, F, G, L, FAAP20, and FAAP100) activates the Fanconi pathway by providing the essential E3 ligase activity for FANCD2 mono-ubiquitination. Previous studies suggested the existence of three protein-protein interaction groups. However, the functions of most FA core complex protein are still limited to their presence in the complex. How the spatially-defined FANCD2 ubiquitination is accomplished by the core complex remains unknown.
To elucidate the roles of FA core complex proteins in ICL response, especially their contribution to FANCD2 ubiquitination, we established isogenic knockout mutants deficient in FA core genes and determined the loss-of-function effects on the activation of FA pathway and on cellular survival against ICLs. Our results suggest three potential functional modules in the FA core complex: FANCB-FANCL-FAAP100 (B-L-100), FANCA-FANCG-FAAP20 (A-G-20), and FANC-FANCE-FANCF (C-E-F). We showed that the B-L-100 sub complex is the catalytic module absolutely required for the E3 ligase function of FA core complex. The A-G-20 module anchors the catalytic module to the chromatin. The C-E-F module acts as a loading factor of the core complex through FANCM. Our work revealed that the FA core complex is assembled with functional modules and carries out the spatially-defined FANCD2 monoubiquitination reaction to ensure that nucleases for DNA damage processing are enriched at the site of lesion. The deviate functions of different FA core complementation groups imply differential disease biology related to prognosis and treatment.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/429"],"dc:subject":["Fanconi anemia","interstrand crosslink","DNA repair","Cancer Biology","Medical Genetics","Molecular Genetics"],"dc:title":["Modulated Functions of The Fanconi Anemia Core Complex"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:49:54Z"}