Abstract
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.
| Original language | English |
|---|---|
| Journal | Molecular Cell |
| Volume | 40 |
| Issue number | 4 |
| Pages (from-to) | 632-44 |
| Number of pages | 13 |
| ISSN | 1097-4164 |
| DOIs | |
| Publication status | Published - 24 Nov 2010 |
Keywords
- Amino Acid Sequence
- Cell Cycle Proteins
- Cell Line
- Cell Survival
- Computational Biology
- DNA Breaks, Double-Stranded
- DNA-Binding Proteins
- DNA-Directed DNA Polymerase
- Drug Resistance
- Humans
- Models, Biological
- Molecular Sequence Data
- Multienzyme Complexes
- Multiprotein Complexes
- NF-kappa B
- Nuclear Proteins
- Protein Binding
- Rad51 Recombinase
- Recombination, Genetic
- S Phase