TY - JOUR
T1 - FANCD2 Facilitates Replication through Common Fragile Sites
AU - Madireddy, Advaitha
AU - Kosiyatrakul, Settapong T.
AU - Boisvert, Rebecca A.
AU - Herrera-Moyano, Emilia
AU - García-Rubio, María L.
AU - Gerhardt, Jeannine
AU - Vuono, Elizabeth A.
AU - Owen, Nichole
AU - Yan, Zi
AU - Olson, Susan
AU - Aguilera, Andrés
AU - Howlett, Niall G.
AU - Schildkraut, Carl L.
N1 - Funding Information:
We thank Paul R. Andreassen at Cincinnati Children’s Hospital Medical Center for PD20 lymphoblasts stably complemented with wild-type FANCD2 or monoubiquitination-defective FANCD2-K561R. We thank Dr. William C. Drosopoulos for editing the manuscript and Grace Wang for helping with data collection. This work was supported by National Institute of General Medical Sciences grant 5R01-GM045751 and Empire State Stem Cell Fund through New York State contract C024348 and the Tri-Institutional Stem Cell Initiative, funded by the Starr Foundation to C.L.S.; National Heart, Lung, and Blood Institute grant R01HL101977 to N.G.H.; and Spanish Ministry of Economy and Competitiveness BFU2013-15687 and European ERC-2014-ADG 669898 TARLOOP grants to A.A.
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/10/20
Y1 - 2016/10/20
N2 - 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.
AB - 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.
KW - DNA replication
KW - DNA:RNA hybrids
KW - Fanconi anemia
KW - cancer
KW - common fragile sites
KW - genomic instability
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U2 - 10.1016/j.molcel.2016.09.017
DO - 10.1016/j.molcel.2016.09.017
M3 - Article
C2 - 27768874
AN - SCOPUS:84994802487
SN - 1097-2765
VL - 64
SP - 388
EP - 404
JO - Molecular Cell
JF - Molecular Cell
IS - 2
ER -
