title: FANCD2 regulates BLM complex functions independently of FANCI to promote replication fork recovery.
abstract: Fanconi Anemia (FA) and Bloom Syndrome share overlapping phenotypes including spontaneous chromosomal abnormalities and increased cancer predisposition. The FA protein pathway comprises an upstream core complex that mediates recruitment of two central players, FANCD2 and FANCI, to sites of stalled replication forks. Successful fork recovery depends on the Bloom's helicase BLM that participates in a larger protein complex ('BLMcx') containing topoisomerase III alpha, RMI1, RMI2 and replication protein A. We show that FANCD2 is an essential regulator of BLMcx functions: it maintains BLM protein stability and is crucial for complete BLMcx assembly; moreover, it recruits BLMcx to replicating chromatin during normal S-phase and mediates phosphorylation of BLMcx members in response to DNA damage. During replication stress, FANCD2 and BLM cooperate to promote restart of stalled replication forks while suppressing firing of new replication origins. In contrast, FANCI is dispensable for FANCD2-dependent BLMcx regulation, demonstrating functional separation of FANCD2 from FANCI.
authors: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
authors: Indrajit
authors: I
authors: Chaudhury
authors: Archana
authors: A
authors: Sareen
authors: Maya
authors: M
authors: Raghunandan
authors: Alexandra
authors: A
authors: Sobeck
mesh_terms: D000818:Animals; D005075:Biological Evolution; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D004261:DNA Replication; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism*; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D053484:RecQ Helicases / Q000378:metabolism*; D051716:Replication Protein A / Q000378:metabolism; D054875:Ubiquitination; D014982:Xenopus laevis
chemical_list: D002843:Chromatin; C519921:FANCI protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D051856:Fanconi Anemia Complementation Group Proteins; D051716:Replication Protein A; C097151:Bloom syndrome protein; D053484:RecQ Helicases
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