Identification of the MMS22L-TONSL complex that promotes homologous recombination.
Budding yeast Mms22 is required for homologous recombination (HR)-mediated repair of stalled or broken DNA replication forks. Here we identify a human Mms22-like protein (MMS22L) and an MMS22L-interacting protein, NFκBIL2/TONSL. Depletion of MMS22L or TONSL from human cells causes a high level of double-strand breaks (DSBs) during DNA replication. Both proteins accumulate at stressed replication forks, and depletion of MMS22L or TONSL from cells causes hypersensitivity to agents that cause S phase-associated DSBs, such as topoisomerase (TOP) inhibitors. In this light, MMS22L and TONSL are required for the HR-mediated repair of replication fork-associated DSBs. In cells depleted of either protein, DSBs induced by the TOP1 inhibitor camptothecin are resected normally, but the loading of the RAD51 recombinase is defective. Therefore, MMS22L and TONSL are required for the maintenance of genome stability when unscheduled DSBs occur in the vicinity of DNA replication forks.
MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.
Eris
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Duro
Cecilia
C
Lundin
Katrine
K
Ask
Luis
L
Sanchez-Pulido
Thomas J
TJ
MacArtney
Rachel
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Toth
Chris P
CP
Ponting
Anja
A
Groth
Thomas
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Helleday
John
J
Rouse
D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D019295:Computational Biology; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase; D004351:Drug Resistance; D006801:Humans; D008954:Models, Biological; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes; D046912:Multiprotein Complexes / Q000378:metabolism*; D016328:NF-kappa B / Q000737:chemistry / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D051135:Rad51 Recombinase / Q000378:metabolism; D011995:Recombination, Genetic; D016196:S Phase; D000099272:Replisomes
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase; D018832:Molecular Chaperones; D009097:Multienzyme Complexes; D046912:Multiprotein Complexes; D016328:NF-kappa B; D009687:Nuclear Proteins; D051135:Rad51 Recombinase; D000099272:Replisomes; C491641:ASF1A protein, human; C491640:ASF1B protein, human; C554517:MMS22L protein, human; C093394:TONSL protein, human