A genome-wide camptothecin sensitivity screen identifies a mammalian MMS22L-NFKBIL2 complex required for genomic stability.

TitleA genome-wide camptothecin sensitivity screen identifies a mammalian MMS22L-NFKBIL2 complex required for genomic stability.
Publication TypeJournal Article
Year of Publication2010
AuthorsO'Connell, BC, Adamson, B, Lydeard, JR, Sowa, ME, Ciccia, A, Bredemeyer, AL, Schlabach, M, Gygi, SP, Elledge, SJ, J Harper, W
JournalMol Cell
Volume40
Issue4
Pagination645-57
Date Published2010 Nov 24
ISSN1097-4164
KeywordsCamptothecin, DNA Damage, DNA Repair, DNA Replication, DNA-Binding Proteins, DNA-Directed DNA Polymerase, Drug Resistance, Neoplasm, Genetic Testing, Genome, Human, Genomic Instability, HeLa Cells, Histones, Humans, Intracellular Signaling Peptides and Proteins, Multienzyme Complexes, NF-kappa B, Nuclear Proteins, Phosphorylation, Protein Binding, Recombination, Genetic, Replication Protein A, Reproducibility of Results, RNA, Small Interfering, Stress, Physiological, Tumor Suppressor p53-Binding Protein 1
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 (minichromosome 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.

DOI10.1016/j.molcel.2010.10.022
Alternate JournalMol. Cell
PubMed ID21055985
PubMed Central IDPMC3006237
Grant ListR01 GM070565-07 / GM / NIGMS NIH HHS / United States
R01 AG011085-18 / AG / NIA NIH HHS / United States
AG011085 / AG / NIA NIH HHS / United States
R01 GM070565-06 / GM / NIGMS NIH HHS / United States
R01 AG011085-17 / AG / NIA NIH HHS / United States
R01 AG011085 / AG / NIA NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R01 GM070565 / GM / NIGMS NIH HHS / United States
R01 AG011085-16 / AG / NIA NIH HHS / United States
GM054137 / GM / NIGMS NIH HHS / United States
R01 GM054137 / GM / NIGMS NIH HHS / United States