Fanconi anemia proteins stabilize replication forks

Lily Chien Wang; Stacie Stone; Maureen Elizabeth Hoatlin; Jean Gautier

doi:10.1016/j.dnarep.2008.08.005

Fanconi anemia proteins stabilize replication forks

Lily Chien Wang
, Stacie Stone
, Maureen Elizabeth Hoatlin
, Jean Gautier

Biochemistry & Molecular Biology

Research output: Contribution to journal › Article › peer-review

61 Scopus citations

Abstract

Fanconi anemia (FA) is a recessive genetic disorder characterized by hypersensitivity to crosslinking agents that has been attributed to defects in DNA repair and/or replication. FANCD2 and the FA core complex bind to chromatin during DNA replication; however, the role of FA proteins during replication is unknown. Using Xenopus cell-free extracts, we show that FANCL depletion results in defective DNA replication restart following treatment with camptothecin, a drug that results in DSBs during DNA replication. This defect is more pronounced following treatment with mitomycin C, presumably because of an additional role of the FA pathway in DNA crosslink repair. Moreover, we show that chromatin binding of FA core complex proteins during DNA replication follows origin assembly and origin firing and is dependent on the binding of RPA to ssDNA while FANCD2 additionally requires ATR, consistent with FA proteins acting at replication forks. Together, our data suggest that FA proteins play a role in replication restart at collapsed replication forks.

Original language	English (US)
Pages (from-to)	1973-1981
Number of pages	9
Journal	DNA Repair
Volume	7
Issue number	12
DOIs	https://doi.org/10.1016/j.dnarep.2008.08.005
State	Published - Dec 1 2008

Funding

We thank Dr. P. Jackson, Dr. W.M. Michael, Dr. T. Wang, and Dr. V. Costanzo for anti-RPA p70, anti-Polα, and anti-ATR antibodies. We thank Dr. M. Wold for the RPA construct. This work was supported by NIH grant CA92245 to JG.

Funders	Funder number
Author National Institutes of Health National Institutes of Health National Institutes of Health National Institutes of Health The Bev Hartig Huntington's Disease Foundation National Institutes of Health	CA92245
National Institute of General Medical Sciences	R01GM077495

Keywords

Fanconi anemia
Mitomycin C
Replication forks
Replication restart

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Cell Biology

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10.1016/j.dnarep.2008.08.005

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title = "Fanconi anemia proteins stabilize replication forks",

abstract = "Fanconi anemia (FA) is a recessive genetic disorder characterized by hypersensitivity to crosslinking agents that has been attributed to defects in DNA repair and/or replication. FANCD2 and the FA core complex bind to chromatin during DNA replication; however, the role of FA proteins during replication is unknown. Using Xenopus cell-free extracts, we show that FANCL depletion results in defective DNA replication restart following treatment with camptothecin, a drug that results in DSBs during DNA replication. This defect is more pronounced following treatment with mitomycin C, presumably because of an additional role of the FA pathway in DNA crosslink repair. Moreover, we show that chromatin binding of FA core complex proteins during DNA replication follows origin assembly and origin firing and is dependent on the binding of RPA to ssDNA while FANCD2 additionally requires ATR, consistent with FA proteins acting at replication forks. Together, our data suggest that FA proteins play a role in replication restart at collapsed replication forks.",

keywords = "Fanconi anemia, Mitomycin C, Replication forks, Replication restart",

author = "Wang, \{Lily Chien\} and Stacie Stone and Hoatlin, \{Maureen Elizabeth\} and Jean Gautier",

note = "Funding Information: We thank Dr. P. Jackson, Dr. W.M. Michael, Dr. T. Wang, and Dr. V. Costanzo for anti-RPA p70, anti-Polα, and anti-ATR antibodies. We thank Dr. M. Wold for the RPA construct. This work was supported by NIH grant CA92245 to JG. ",

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doi = "10.1016/j.dnarep.2008.08.005",

language = "English (US)",

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T1 - Fanconi anemia proteins stabilize replication forks

AU - Wang, Lily Chien

AU - Stone, Stacie

AU - Hoatlin, Maureen Elizabeth

AU - Gautier, Jean

N1 - Funding Information: We thank Dr. P. Jackson, Dr. W.M. Michael, Dr. T. Wang, and Dr. V. Costanzo for anti-RPA p70, anti-Polα, and anti-ATR antibodies. We thank Dr. M. Wold for the RPA construct. This work was supported by NIH grant CA92245 to JG.

PY - 2008/12/1

Y1 - 2008/12/1

N2 - Fanconi anemia (FA) is a recessive genetic disorder characterized by hypersensitivity to crosslinking agents that has been attributed to defects in DNA repair and/or replication. FANCD2 and the FA core complex bind to chromatin during DNA replication; however, the role of FA proteins during replication is unknown. Using Xenopus cell-free extracts, we show that FANCL depletion results in defective DNA replication restart following treatment with camptothecin, a drug that results in DSBs during DNA replication. This defect is more pronounced following treatment with mitomycin C, presumably because of an additional role of the FA pathway in DNA crosslink repair. Moreover, we show that chromatin binding of FA core complex proteins during DNA replication follows origin assembly and origin firing and is dependent on the binding of RPA to ssDNA while FANCD2 additionally requires ATR, consistent with FA proteins acting at replication forks. Together, our data suggest that FA proteins play a role in replication restart at collapsed replication forks.

AB - Fanconi anemia (FA) is a recessive genetic disorder characterized by hypersensitivity to crosslinking agents that has been attributed to defects in DNA repair and/or replication. FANCD2 and the FA core complex bind to chromatin during DNA replication; however, the role of FA proteins during replication is unknown. Using Xenopus cell-free extracts, we show that FANCL depletion results in defective DNA replication restart following treatment with camptothecin, a drug that results in DSBs during DNA replication. This defect is more pronounced following treatment with mitomycin C, presumably because of an additional role of the FA pathway in DNA crosslink repair. Moreover, we show that chromatin binding of FA core complex proteins during DNA replication follows origin assembly and origin firing and is dependent on the binding of RPA to ssDNA while FANCD2 additionally requires ATR, consistent with FA proteins acting at replication forks. Together, our data suggest that FA proteins play a role in replication restart at collapsed replication forks.

KW - Fanconi anemia

KW - Mitomycin C

KW - Replication forks

KW - Replication restart

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UR - https://www.scopus.com/pages/publications/55149115113#tab=citedBy

U2 - 10.1016/j.dnarep.2008.08.005

DO - 10.1016/j.dnarep.2008.08.005

M3 - Article

C2 - 18786657

AN - SCOPUS:55149115113

SN - 1568-7864

VL - 7

SP - 1973

EP - 1981

JO - DNA Repair

JF - DNA Repair

IS - 12

ER -

Fanconi anemia proteins stabilize replication forks

Abstract

Funding

Keywords

ASJC Scopus subject areas

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