@article{3404, keywords = {Stress, Physiological, Nuclear Proteins, Humans, Protein Binding, HeLa Cells, Phosphorylation, DNA-Binding Proteins, Reproducibility of Results, RNA, Small Interfering, DNA Damage, Drug Resistance, Neoplasm, Histones, Genome, Human, DNA Replication, DNA Repair, Recombination, Genetic, Intracellular Signaling Peptides and Proteins, Genomic Instability, Camptothecin, DNA-Directed DNA Polymerase, Genetic Testing, Multienzyme Complexes, NF-kappa B, Replication Protein A, Tumor Suppressor p53-Binding Protein 1}, author = {Brenda O{\textquoteright}Connell and Britt Adamson and John Lydeard and Mathew Sowa and Alberto Ciccia and Andrea Bredemeyer and Michael Schlabach and Steven Gygi and Stephen Elledge and J Wade Harper}, 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 (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.
}, year = {2010}, journal = {Mol Cell}, volume = {40}, pages = {645-57}, month = {2010 Nov 24}, issn = {1097-4164}, doi = {10.1016/j.molcel.2010.10.022}, language = {eng}, }