title: FANCD2 Facilitates Replication through Common Fragile Sites.
abstract: Common fragile sites (CFSs) are genomic regions that are unstable under conditions of replicative stress. Although the characteristics of CFSs that render them vulnerable to stress are associated mainly with replication, the cellular pathways that protect CFSs during replication remain unclear. Here, we identify and describe a role for FANCD2 as a trans-acting facilitator of CFS replication, in the absence of exogenous replicative stress. In the absence of FANCD2, replication forks stall within the AT-rich fragility core of CFS, leading to dormant origin activation. Furthermore, FANCD2 deficiency is associated with DNA:RNA hybrid formation at CFS-FRA16D, and inhibition of DNA:RNA hybrid formation suppresses replication perturbation. In addition, we also found that FANCD2 reduces the number of potential sites of replication initiation. Our data demonstrate that FANCD2 protein is required to ensure efficient CFS replication and provide mechanistic insight into how FANCD2 regulates CFS stability.
authors: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: advaitha@gmail.com.
authors: Advaitha
authors: A
authors: Madireddy
authors: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Settapong T
authors: ST
authors: Kosiyatrakul
authors: Department of Cell and Molecular Biology, University of Rhode Island, Kingston, RI 02881, USA.
authors: Rebecca A
authors: RA
authors: Boisvert
authors: Centro Andaluz de Biología Molecular y Medicina Regenerativa, Universidad de Sevilla, 41092 Seville, Spain.
authors: Emilia
authors: E
authors: Herrera-Moyano
authors: Centro Andaluz de Biología Molecular y Medicina Regenerativa, Universidad de Sevilla, 41092 Seville, Spain.
authors: María L
authors: ML
authors: García-Rubio
authors: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Jeannine
authors: J
authors: Gerhardt
authors: Department of Cell and Molecular Biology, University of Rhode Island, Kingston, RI 02881, USA.
authors: Elizabeth A
authors: EA
authors: Vuono
authors: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Nichole
authors: N
authors: Owen
authors: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Zi
authors: Z
authors: Yan
authors: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Susan
authors: S
authors: Olson
authors: Centro Andaluz de Biología Molecular y Medicina Regenerativa, Universidad de Sevilla, 41092 Seville, Spain.
authors: Andrés
authors: A
authors: Aguilera
authors: Department of Cell and Molecular Biology, University of Rhode Island, Kingston, RI 02881, USA.
authors: Niall G
authors: NG
authors: Howlett
authors: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: schildkr@aecom.yu.edu.
authors: Carl L
authors: CL
authors: Schildkraut
mesh_terms: D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D043283:Chromosome Fragile Sites; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D004261:DNA Replication; D005199:Fanconi Anemia; D052217:Fanconi Anemia Complementation Group A Protein / Q000235:genetics / Q000378:metabolism; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics* / Q000378:metabolism; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D042822:Genomic Instability; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D012313:RNA / Q000235:genetics* / Q000378:metabolism
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C498471:FANCA protein, human; C499905:FANCD2 protein, human; C519921:FANCI protein, human; D052217:Fanconi Anemia Complementation Group A Protein; D052236:Fanconi Anemia Complementation Group D2 Protein; D051856:Fanconi Anemia Complementation Group Proteins; D012313:RNA; D004247:DNA
keywords: DNA replication; DNA:RNA hybrids; Fanconi anemia; cancer; common fragile sites; genomic instability