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Mol Cell. 2016 Oct 20;64(2):388-404. doi: 10.1016/j.molcel.2016.09.017.

FANCD2 Facilitates Replication through Common Fragile Sites.

Author information

1
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: advaitha@gmail.com.
2
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
3
Department of Cell and Molecular Biology, University of Rhode Island, Kingston, RI 02881, USA.
4
Centro Andaluz de Biología Molecular y Medicina Regenerativa, Universidad de Sevilla, 41092 Seville, Spain.
5
Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA.
6
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: schildkr@aecom.yu.edu.

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.

KEYWORDS:

DNA replication; DNA:RNA hybrids; Fanconi anemia; cancer; common fragile sites; genomic instability

PMID:
27768874
PMCID:
PMC5683400
DOI:
10.1016/j.molcel.2016.09.017
[Indexed for MEDLINE]
Free PMC Article

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