FANCM and FAAP24 Maintain Genome Stability via Cooperative as Well as Unique Functions

Yucai Wang; Justin W. Leung; Yingjun Jiang; Megan G. Lowery; Huong Do; Karen M. Vasquez; Junjie Chen; Weidong Wang; Lei Li

doi:10.1016/j.molcel.2012.12.010

FANCM and FAAP24 Maintain Genome Stability via Cooperative as Well as Unique Functions

Yucai Wang, Justin W. Leung, Yingjun Jiang, Megan G. Lowery, Huong Do, Karen M. Vasquez, Junjie Chen, Weidong Wang, Lei Li

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

64 Scopus citations

Abstract

The DNA remodeling enzyme FANCM and its DNA-binding partner, FAAP24, constitute a complex involved in the activation of Fanconi anemia (FA) DNA damage response mechanism, but neither gene has distinct patient mutants. In this study, we created isogenic models for both FANCM and FAAP24 and investigated their integrated functions in DNA damage response. We found that FANCM and FAAP24 coordinately facilitate FA pathway activation and suppress sister chromatid exchange. Importantly, we show that FANCM and FAAP24 possess nonoverlapping functions such that FAAP24 promotes ATR-mediated checkpoint activation particularly in response to DNA crosslinking agents, whereas FANCM participates in recombination-independent interstrand crosslink repair by facilitating recruitment of lesion incision activities, which requires its translocase activity. Our data suggest that FANCM and FAAP24 play multiple, while not fully epistatic, roles in maintaining genomic integrity.

Original language	English (US)
Pages (from-to)	997-1009
Number of pages	13
Journal	Molecular cell
Volume	49
Issue number	5
DOIs	https://doi.org/10.1016/j.molcel.2012.12.010
State	Published - Mar 7 2013

ASJC Scopus subject areas

Molecular Biology
Cell Biology

MD Anderson CCSG core facilities

Flow Cytometry and Cellular Imaging Facility

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10.1016/j.molcel.2012.12.010

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title = "FANCM and FAAP24 Maintain Genome Stability via Cooperative as Well as Unique Functions",

abstract = "The DNA remodeling enzyme FANCM and its DNA-binding partner, FAAP24, constitute a complex involved in the activation of Fanconi anemia (FA) DNA damage response mechanism, but neither gene has distinct patient mutants. In this study, we created isogenic models for both FANCM and FAAP24 and investigated their integrated functions in DNA damage response. We found that FANCM and FAAP24 coordinately facilitate FA pathway activation and suppress sister chromatid exchange. Importantly, we show that FANCM and FAAP24 possess nonoverlapping functions such that FAAP24 promotes ATR-mediated checkpoint activation particularly in response to DNA crosslinking agents, whereas FANCM participates in recombination-independent interstrand crosslink repair by facilitating recruitment of lesion incision activities, which requires its translocase activity. Our data suggest that FANCM and FAAP24 play multiple, while not fully epistatic, roles in maintaining genomic integrity.",

author = "Yucai Wang and Leung, {Justin W.} and Yingjun Jiang and Lowery, {Megan G.} and Huong Do and Vasquez, {Karen M.} and Junjie Chen and Weidong Wang and Lei Li",

note = "Funding Information: The authors wish to thank Dr. Zhenghe Wang for providing reagents and technical advice on rAAV-based targeting and Drs. Lee Zou and Junran Zhang for technical advices on RPA2 immunostaining. This work was supported in part by the Intramural Research Program of the National Institute on Aging (AG000688-07), National Institute of Health (W.W.) and by grants from CPRIT (Multi-Investigator Award; RP110465-P2 to J.C.) and the National Cancer Institute (CA127945 and CA097175 Project 3 to L.L). eChIP substrates preparation and clonogenic survivals were assisted respectively by Core C and Core B (CA097175). J.C. is a recipient of an Era of Hope Scholar award from the Department of Defense (W81XWH-05-1-0470). ",

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T1 - FANCM and FAAP24 Maintain Genome Stability via Cooperative as Well as Unique Functions

AU - Wang, Yucai

AU - Leung, Justin W.

AU - Jiang, Yingjun

AU - Lowery, Megan G.

AU - Do, Huong

AU - Vasquez, Karen M.

AU - Chen, Junjie

AU - Wang, Weidong

AU - Li, Lei

N1 - Funding Information: The authors wish to thank Dr. Zhenghe Wang for providing reagents and technical advice on rAAV-based targeting and Drs. Lee Zou and Junran Zhang for technical advices on RPA2 immunostaining. This work was supported in part by the Intramural Research Program of the National Institute on Aging (AG000688-07), National Institute of Health (W.W.) and by grants from CPRIT (Multi-Investigator Award; RP110465-P2 to J.C.) and the National Cancer Institute (CA127945 and CA097175 Project 3 to L.L). eChIP substrates preparation and clonogenic survivals were assisted respectively by Core C and Core B (CA097175). J.C. is a recipient of an Era of Hope Scholar award from the Department of Defense (W81XWH-05-1-0470).

PY - 2013/3/7

Y1 - 2013/3/7

N2 - The DNA remodeling enzyme FANCM and its DNA-binding partner, FAAP24, constitute a complex involved in the activation of Fanconi anemia (FA) DNA damage response mechanism, but neither gene has distinct patient mutants. In this study, we created isogenic models for both FANCM and FAAP24 and investigated their integrated functions in DNA damage response. We found that FANCM and FAAP24 coordinately facilitate FA pathway activation and suppress sister chromatid exchange. Importantly, we show that FANCM and FAAP24 possess nonoverlapping functions such that FAAP24 promotes ATR-mediated checkpoint activation particularly in response to DNA crosslinking agents, whereas FANCM participates in recombination-independent interstrand crosslink repair by facilitating recruitment of lesion incision activities, which requires its translocase activity. Our data suggest that FANCM and FAAP24 play multiple, while not fully epistatic, roles in maintaining genomic integrity.

AB - The DNA remodeling enzyme FANCM and its DNA-binding partner, FAAP24, constitute a complex involved in the activation of Fanconi anemia (FA) DNA damage response mechanism, but neither gene has distinct patient mutants. In this study, we created isogenic models for both FANCM and FAAP24 and investigated their integrated functions in DNA damage response. We found that FANCM and FAAP24 coordinately facilitate FA pathway activation and suppress sister chromatid exchange. Importantly, we show that FANCM and FAAP24 possess nonoverlapping functions such that FAAP24 promotes ATR-mediated checkpoint activation particularly in response to DNA crosslinking agents, whereas FANCM participates in recombination-independent interstrand crosslink repair by facilitating recruitment of lesion incision activities, which requires its translocase activity. Our data suggest that FANCM and FAAP24 play multiple, while not fully epistatic, roles in maintaining genomic integrity.

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FANCM and FAAP24 Maintain Genome Stability via Cooperative as Well as Unique Functions

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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