A Genome-wide Camptothecin Sensitivity Screen Identifies a Mammalian MMS22L-NFKBIL2 Complex Required for Genomic Stability

Brenda C. O'Connell; Britt Adamson; John R. Lydeard; Mathew E. Sowa; Alberto Ciccia; Andrea L. Bredemeyer; Michael Schlabach; Steven P. Gygi; Stephen J. Elledge; J. W. Harper

doi:10.1016/j.molcel.2010.10.022

A Genome-wide Camptothecin Sensitivity Screen Identifies a Mammalian MMS22L-NFKBIL2 Complex Required for Genomic Stability

Brenda C. O'Connell, Britt Adamson, John R. Lydeard, Mathew E. Sowa, Alberto Ciccia, Andrea L. Bredemeyer, Michael Schlabach, Steven P. Gygi, Stephen J. Elledge, J. W. Harper

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

97 Scopus citations

Abstract

Replication stress involving collision of replisomes with camptothecin (CPT)-stabilized DNA-Topoisomerase I adducts activates an ATR-dependent pathway to promote repair by homologous recombination. To identify human genes that protect cells from such replication stress, we performed a genome-wide CPT sensitivity screen. Among numerous candidate genes are two previously unstudied proteins: the ankyrin repeat protein NFKBIL2 and C6ORF167 (MMS22L), distantly related to yeast replication stress regulator Mms22p. MMS22L and NFKBIL2 interact with each other and with FACT (facilitator of chromatin transcription) and MCM (mini. chromosome maintenance) complexes. Cells depleted of NFKBIL2 or MMS22L are sensitive to DNA-damaging agents, load phosphorylated RPA onto chromatin in a CTIP-dependent manner, activate the ATR/ATRIP-CHK1 and double-strand break repair signaling pathways, and are defective in HR. This study identifies MMS22L-NFKBIL2 as components of the replication stress control pathway and provides a resource for discovery of additional components of this pathway.

Original language	English (US)
Pages (from-to)	645-657
Number of pages	13
Journal	Molecular Cell
Volume	40
Issue number	4
DOIs	https://doi.org/10.1016/j.molcel.2010.10.022
State	Published - Nov 24 2010
Externally published	Yes

All Science Journal Classification (ASJC) codes

Molecular Biology
Cell Biology

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10.1016/j.molcel.2010.10.022

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@article{8dd0490ef00844c9b9f83c50c7833f2e,

title = "A Genome-wide Camptothecin Sensitivity Screen Identifies a Mammalian MMS22L-NFKBIL2 Complex Required for Genomic Stability",

abstract = "Replication stress involving collision of replisomes with camptothecin (CPT)-stabilized DNA-Topoisomerase I adducts activates an ATR-dependent pathway to promote repair by homologous recombination. To identify human genes that protect cells from such replication stress, we performed a genome-wide CPT sensitivity screen. Among numerous candidate genes are two previously unstudied proteins: the ankyrin repeat protein NFKBIL2 and C6ORF167 (MMS22L), distantly related to yeast replication stress regulator Mms22p. MMS22L and NFKBIL2 interact with each other and with FACT (facilitator of chromatin transcription) and MCM (mini. chromosome maintenance) complexes. Cells depleted of NFKBIL2 or MMS22L are sensitive to DNA-damaging agents, load phosphorylated RPA onto chromatin in a CTIP-dependent manner, activate the ATR/ATRIP-CHK1 and double-strand break repair signaling pathways, and are defective in HR. This study identifies MMS22L-NFKBIL2 as components of the replication stress control pathway and provides a resource for discovery of additional components of this pathway.",

author = "O'Connell, {Brenda C.} and Britt Adamson and Lydeard, {John R.} and Sowa, {Mathew E.} and Alberto Ciccia and Bredemeyer, {Andrea L.} and Michael Schlabach and Gygi, {Steven P.} and Elledge, {Stephen J.} and Harper, {J. W.}",

note = "Funding Information: We thank L. Zou (MGH Cancer Center) for helpful discussions, and D. Durocher, J. Rouse, and M. Peter for communicating results prior to publication. We thank G. Nalepa for help during initial stages of the project as well as intellectual support and J. Hernandez for technical support. This work was supported by National Institutes of Health (NIH) grants AG011085 and GM054137, and by a grant from the Stewart Trust to J.W.H. Additional support was provided by a grant from the NIH to S.J.E. B.C.O. was supported by a fellowship from the American Cancer Society. S.J.E. is an investigator of the Howard Hughes Medical Institute. ",

year = "2010",

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doi = "10.1016/j.molcel.2010.10.022",

language = "English (US)",

volume = "40",

pages = "645--657",

journal = "Molecular Cell",

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T1 - A Genome-wide Camptothecin Sensitivity Screen Identifies a Mammalian MMS22L-NFKBIL2 Complex Required for Genomic Stability

AU - O'Connell, Brenda C.

AU - Adamson, Britt

AU - Lydeard, John R.

AU - Sowa, Mathew E.

AU - Ciccia, Alberto

AU - Bredemeyer, Andrea L.

AU - Schlabach, Michael

AU - Gygi, Steven P.

AU - Elledge, Stephen J.

AU - Harper, J. W.

N1 - Funding Information: We thank L. Zou (MGH Cancer Center) for helpful discussions, and D. Durocher, J. Rouse, and M. Peter for communicating results prior to publication. We thank G. Nalepa for help during initial stages of the project as well as intellectual support and J. Hernandez for technical support. This work was supported by National Institutes of Health (NIH) grants AG011085 and GM054137, and by a grant from the Stewart Trust to J.W.H. Additional support was provided by a grant from the NIH to S.J.E. B.C.O. was supported by a fellowship from the American Cancer Society. S.J.E. is an investigator of the Howard Hughes Medical Institute.

PY - 2010/11/24

Y1 - 2010/11/24

N2 - Replication stress involving collision of replisomes with camptothecin (CPT)-stabilized DNA-Topoisomerase I adducts activates an ATR-dependent pathway to promote repair by homologous recombination. To identify human genes that protect cells from such replication stress, we performed a genome-wide CPT sensitivity screen. Among numerous candidate genes are two previously unstudied proteins: the ankyrin repeat protein NFKBIL2 and C6ORF167 (MMS22L), distantly related to yeast replication stress regulator Mms22p. MMS22L and NFKBIL2 interact with each other and with FACT (facilitator of chromatin transcription) and MCM (mini. chromosome maintenance) complexes. Cells depleted of NFKBIL2 or MMS22L are sensitive to DNA-damaging agents, load phosphorylated RPA onto chromatin in a CTIP-dependent manner, activate the ATR/ATRIP-CHK1 and double-strand break repair signaling pathways, and are defective in HR. This study identifies MMS22L-NFKBIL2 as components of the replication stress control pathway and provides a resource for discovery of additional components of this pathway.

AB - Replication stress involving collision of replisomes with camptothecin (CPT)-stabilized DNA-Topoisomerase I adducts activates an ATR-dependent pathway to promote repair by homologous recombination. To identify human genes that protect cells from such replication stress, we performed a genome-wide CPT sensitivity screen. Among numerous candidate genes are two previously unstudied proteins: the ankyrin repeat protein NFKBIL2 and C6ORF167 (MMS22L), distantly related to yeast replication stress regulator Mms22p. MMS22L and NFKBIL2 interact with each other and with FACT (facilitator of chromatin transcription) and MCM (mini. chromosome maintenance) complexes. Cells depleted of NFKBIL2 or MMS22L are sensitive to DNA-damaging agents, load phosphorylated RPA onto chromatin in a CTIP-dependent manner, activate the ATR/ATRIP-CHK1 and double-strand break repair signaling pathways, and are defective in HR. This study identifies MMS22L-NFKBIL2 as components of the replication stress control pathway and provides a resource for discovery of additional components of this pathway.

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JO - Molecular Cell

JF - Molecular Cell

IS - 4

ER -

A Genome-wide Camptothecin Sensitivity Screen Identifies a Mammalian MMS22L-NFKBIL2 Complex Required for Genomic Stability

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