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

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2010 Nov 9

PMID 21055985

Citations 77

Authors

Brenda C OConnell

Britt Adamson

John R Lydeard

Mathew E Sowa

Alberto Ciccia

Andrea L Bredemeyer

Michael Schlabach

Steven P Gygi

Stephen J Elledge

J Wade Harper

Affiliations

Soon will be listed here.

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.

Citing Articles

MUSICiAn: Genome-wide Identification of Genes Involved in DNA Repair via Control-Free Mutational Spectra Analysis.

Seale C, Barazas M, van Schendel R, Tijsterman M, Goncalves J bioRxiv. 2025; .

PMID: 39975194 PMC: 11838396. DOI: 10.1101/2025.01.27.635038.

Carboplatin-resistance-related DNA damage repair prognostic gene signature and its association with immune infiltration in breast cancer.

Dong S, Li A, Pan R, Hong J, Wang Z, Shen K Front Immunol. 2025; 16:1522149.

PMID: 39944694 PMC: 11813922. DOI: 10.3389/fimmu.2025.1522149.

H3.1K27M-induced misregulation of the TSK/TONSL-H3.1 pathway causes genomic instability.

Yuan W, Huang Y, LeBlanc C, Poulet A, Valsakumar D, van Wolfswinkel J bioRxiv. 2024; .

PMID: 39713323 PMC: 11661185. DOI: 10.1101/2024.12.09.627617.

Repair of replication-dependent double-strand breaks differs between the leading and lagging strands.

Kimble M, Sane A, Reid R, Johnson M, Rothstein R, Symington L Mol Cell. 2024; 85(1):61-77.e6.

PMID: 39631395 PMC: 11698654. DOI: 10.1016/j.molcel.2024.10.032.

Topological stress triggers persistent DNA lesions in ribosomal DNA with ensuing formation of PML-nucleolar compartment.

Urbancokova A, Hornofova T, Novak J, Salajkova S, Hubackova S, Uvizl A Elife. 2024; 12.

PMID: 39388244 PMC: 11466457. DOI: 10.7554/eLife.91304.

References

Krebs A, Tora L . Keys to open chromatin for transcription activation: FACT and Asf1. Mol Cell. 2009; 34(4):397-9. DOI: 10.1016/j.molcel.2009.05.004. View

Svendsen J, Smogorzewska A, Sowa M, OConnell B, Gygi S, Elledge S . Mammalian BTBD12/SLX4 assembles a Holliday junction resolvase and is required for DNA repair. Cell. 2009; 138(1):63-77. PMC: 2720686. DOI: 10.1016/j.cell.2009.06.030. View

Friedel A, Pike B, Gasser S . ATR/Mec1: coordinating fork stability and repair. Curr Opin Cell Biol. 2009; 21(2):237-44. DOI: 10.1016/j.ceb.2009.01.017. View

Vasunia K, Connelly M, Anderson C, Dixon K . Sites of UV-induced phosphorylation of the p34 subunit of replication protein A from HeLa cells. J Biol Chem. 1997; 272(38):23896-904. DOI: 10.1074/jbc.272.38.23896. View

Zou L, Cortez D, Elledge S . Regulation of ATR substrate selection by Rad17-dependent loading of Rad9 complexes onto chromatin. Genes Dev. 2002; 16(2):198-208. PMC: 155323. DOI: 10.1101/gad.950302. View

Zou L . Single- and double-stranded DNA: building a trigger of ATR-mediated DNA damage response. Genes Dev. 2007; 21(8):879-85. DOI: 10.1101/gad.1550307. View

Suzuki T, Inagaki S, Nakajima S, Akashi T, Ohto M, Kobayashi M . A novel Arabidopsis gene TONSOKU is required for proper cell arrangement in root and shoot apical meristems. Plant J. 2004; 38(4):673-84. DOI: 10.1111/j.1365-313X.2004.02074.x. View

Chin-Ming Tan B, Chien C, Hirose S, Lee S . Functional cooperation between FACT and MCM helicase facilitates initiation of chromatin DNA replication. EMBO J. 2006; 25(17):3975-85. PMC: 1560368. DOI: 10.1038/sj.emboj.7601271. View

Kim J, Haber J . Chromatin assembly factors Asf1 and CAF-1 have overlapping roles in deactivating the DNA damage checkpoint when DNA repair is complete. Proc Natl Acad Sci U S A. 2009; 106(4):1151-6. PMC: 2633530. DOI: 10.1073/pnas.0812578106. View

10.

Zaidi I, Rabut G, Poveda A, Scheel H, Malmstrom J, Ulrich H . Rtt101 and Mms1 in budding yeast form a CUL4(DDB1)-like ubiquitin ligase that promotes replication through damaged DNA. EMBO Rep. 2008; 9(10):1034-40. PMC: 2572122. DOI: 10.1038/embor.2008.155. View

11.

Cortez D, Guntuku S, Qin J, Elledge S . ATR and ATRIP: partners in checkpoint signaling. Science. 2001; 294(5547):1713-6. DOI: 10.1126/science.1065521. View

12.

Flatten K, Dai N, Vroman B, Loegering D, Erlichman C, Karnitz L . The role of checkpoint kinase 1 in sensitivity to topoisomerase I poisons. J Biol Chem. 2005; 280(14):14349-55. DOI: 10.1074/jbc.M411890200. View

13.

Landais I, Lee H, Lu H . Coupling caspase cleavage and ubiquitin-proteasome-dependent degradation of SSRP1 during apoptosis. Cell Death Differ. 2006; 13(11):1866-78. DOI: 10.1038/sj.cdd.4401878. View

14.

Vassin V, Anantha R, Sokolova E, Kanner S, Borowiec J . Human RPA phosphorylation by ATR stimulates DNA synthesis and prevents ssDNA accumulation during DNA-replication stress. J Cell Sci. 2009; 122(Pt 22):4070-80. PMC: 2776501. DOI: 10.1242/jcs.053702. View

15.

Stokes M, Rush J, MacNeill J, Min Ren J, Sprott K, Nardone J . Profiling of UV-induced ATM/ATR signaling pathways. Proc Natl Acad Sci U S A. 2007; 104(50):19855-60. PMC: 2148387. DOI: 10.1073/pnas.0707579104. View

16.

Ewing R, Chu P, Elisma F, Li H, Taylor P, Climie S . Large-scale mapping of human protein-protein interactions by mass spectrometry. Mol Syst Biol. 2007; 3:89. PMC: 1847948. DOI: 10.1038/msb4100134. View

17.

Costanzo M, Baryshnikova A, Bellay J, Kim Y, Spear E, Sevier C . The genetic landscape of a cell. Science. 2010; 327(5964):425-31. PMC: 5600254. DOI: 10.1126/science.1180823. View

18.

Zou L . Checkpoint Mec-tivation comes in many flavors. Mol Cell. 2009; 36(5):734-5. DOI: 10.1016/j.molcel.2009.11.026. View

19.

Cimprich K, Cortez D . ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol. 2008; 9(8):616-27. PMC: 2663384. DOI: 10.1038/nrm2450. View

20.

Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N . Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell. 2006; 22(6):719-729. DOI: 10.1016/j.molcel.2006.05.022. View