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 journalArticle

72 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 languageEnglish
Pages (from-to)645-657
Number of pages13
JournalMolecular cell
Volume40
Issue number4
DOIs
StatePublished - Nov 24 2010
Externally publishedYes

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    O'Connell, B. C., Adamson, B., Lydeard, J. R., Sowa, M. E., Ciccia, A., Bredemeyer, A. L., Schlabach, M., Gygi, S. P., Elledge, S. J., & Harper, J. W. (2010). A Genome-wide Camptothecin Sensitivity Screen Identifies a Mammalian MMS22L-NFKBIL2 Complex Required for Genomic Stability. Molecular cell, 40(4), 645-657. https://doi.org/10.1016/j.molcel.2010.10.022