The MMS22L–TONSL heterodimer directly promotes RAD51-dependent recombination upon replication stress
Open accessAbstract
Homologous recombination (HR) is a key pathway that repairs DNA double-strand breaks (DSBs) and helps to restart stalled or collapsed replication forks. How HR supports replication upon genotoxic stress is not understood. Using in vivo and in vitro approaches, we show that the MMS22L-TONSL heterodimer localizes to replication forks under unperturbed conditions and its recruitment is increased during replication stress in human cells. MMS22L-TONSL associates with replication protein A (RPA)-coated ssDNA, and the MMS22L subunit directly interacts with the strand exchange protein RAD51. MMS22L is required for proper RAD51 assembly at DNA damage sites in vivo, and HR-mediated repair of stalled forks is abrogated in cells expressing a MMS22L mutant deficient in RAD51 interaction. Similar to the recombination mediator BRCA2, recombinant MMS22L-TONSL limits the assembly of RAD51 on dsDNA, which stimulates RAD51-ssDNA nucleoprotein filament formation and RAD51-dependent strand exchange activity in vitro Thus, by specifically regulating RAD51 activity at uncoupled replication forks, MMS22L-TONSL stabilizes perturbed replication forks by promoting replication fork reversal and stimulating their HR-mediated restart in vivo.
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In proteome wide screens, SPOC readily identified STK19, USP37, and DONSON partners whose function we validated.
“The power of SPOC is illustrated by the fact that in proteome wide screens, it readily identified STK19, USP37, and DONSON partners whose function we validated23,54,56.”
From Predictomes, a classifier-curated database of AlphaFold-modeled protein-protein interactions (2025) · cites this paper as [54]
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“In addition to having a role in promoting normal replication, TONSL also functions to repair and restart damaged replication forks through its ability both to chaperone histones(46,47) and to facilitate RAD51 loading.(40) Consequently, transient depletion of TONSL compromises a cell’s capacity to replicate through DNA…”
BackgroundDNA replication through a chromatin environment
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“Knockdown of TONSL by siRNA treatment in patient cells from SPONASTRIME dysplasia, a rare weak bone disease caused by hypomorphic mutation of TONSL, reduces RAD51 foci upon CPT treatment, revealing its essential role in RAD51’s ability to load to DNA damage sites by interacting with RPA [202,203].”
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“Therefore, it was demonstrated that small interfering RNA (siRNA)-mediated TONSL knockdown leads to the loss of damage-induced RAD51-foci formation in cells treated with genotoxic agents.(11,12,16) In this study, in order to identify the causative genetic alteration for SPONASTRIME dysplasia, we recruited 13 individua…”
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“Recombinant fulllength RAD51 was prepared as described previously (26).”
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“Even so, some loading of RAD51 may occur independently of BRCA2, for example by MMS22L/TONSL [40].”
BackgroundJackson, L. M., Dhoonmoon, A., Hale, A., Dennis, K. A., Schleicher, E. M., Nicolae, C. M., & Moldovan, G. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab1184 · Cited by 27 · see citing works
“A number of BRCA-independent mechanisms of RAD51 loading to DNA breaks have been previously described, including those governed by RAD52 and the TONSL–MMS22L complex (44,45).”
A tough row to hoe: when replication forks encounter DNA damage
Patel, D. R., & Weiss, R. S. (2018) · Biochemical Society Transactions · doi:10.1042/bst20180308 · Cited by 25 · see citing works
“Interestingly, other HR mediators, such as RAD54, the RAD51 paralogs, and MMS22L– TONSL (MMS22-like, DNA repair protein–tonsoku-like, DNA repair protein), support BRCA2-independent RAD51 loading during fork reversal (19, 45, 46).”
BackgroundUbiquitin-mediated DNA damage response is synthetic lethal with G-quadruplex stabilizer CX-5461
Masud, T., Soong, C., Xu, H., Biele, J., Bjornson, S., McKinney, S., & Aparicio, S. (2021) · Scientific Reports · doi:10.1038/s41598-021-88988-w · Cited by 27 · see citing works
Genes and Weightlifting Performance
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“This protein forms a complex with tonsoku-like, DNA repair protein (TONSL), which recognizes and repairs DNA double-strand breaks at sites of stalled or collapsed replication forks [24].”
BackgroundLiu, W., Polaczek, P., Roubal, I., Meng, Y., Choe, W., Caron, M., Sedgeman, C. A., Yu, X., Liu, C., Wu, Q., et al. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad624 · Cited by 22 · see citing works
BRCA2 BRC missense variants disrupt RAD51-dependent DNA repair
Jiménez-Sáinz, J., Mathew, J., Moore, G., Lahiri, S., Garbarino, J. M., Eder, J. P., Rothenberg, E., & Jensen, R. B. (2022) · eLife · doi:10.7554/elife.79183 · Cited by 19 · see citing works
The SOX9-MMS22L Axis Promotes Oxaliplatin Resistance in Colorectal Cancer
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“Further research has shown that MMS22L participates in DNA repair by promoting the displacement of the single-stranded DNA binding protein RPA and assembly of RAD51 filaments at DNA damage sites in response to CPT (Piwko et al., 2016; Huang et al., 2018).”
BackgroundMMS22L-TONSL functions in sister chromatid cohesion in a pathway parallel to DSCC1-RFC
van Schie, J. J. M., de Lint, K., Pai, G. M., Rooimans, M. A., Wolthuis, R. M. F., & de Lange, J. (2022) · Life Science Alliance · doi:10.26508/lsa.202201596 · Cited by 17 · see citing works
“In vertebrate cells, MMS22L interacts with TONSL — a protein which is apparently lacking in yeast — to form a heterodimer that localizes at replication forks and functions in the DNA damage response (Duro et al, 2010; O ’ Connell et al, 2010; O ’ Donnell et al, 2010; Piwko et al, 2016).”
Chromatin as a Platform for Modulating the Replication Stress Response
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“Importantly, recruitment of TONSL–MMS22L to nascent chromatin increases during replication stress [82].”
BackgroundDiao, L., Chen, C., Dennehey, B. K., Pal, S., Wang, P., Shen, Z.-J., Deem, A. K., & Tyler, J. K. (2017) · PLoS ONE · doi:10.1371/journal.pone.0180556 · Cited by 16 · see citing works
Fresh and ozonized black carbon promoted DNA damage and repair responses in A549 cells
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“At the damaged site of a replication fork, TONSL–MMS22L loads Rad51 to replace RPA [6] with”
BackgroundPalek, M., Palková, N., Černá, M., Horáčková, K., Hovhannisyan, M., Janatová, M., Jelínková, S., Nehasil, P., Soukupová, J., Šťastná, B., et al. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae499 · Cited by 12 · see citing works
“Our observations can be likely explained by recognition of the H4K20me0 histone by the highly conserved ARD domain of SLF1 in a similar manner as was described for BARD1 and TONSL ( 10–12 ).”
BackgroundMuraszko, J., Kramarz, K., Argunhan, B., Ito, K., Baranowska, G., Kurokawa, Y., Murayama, Y., Tsubouchi, H., Lambert, S., Iwasaki, H., et al. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab511 · Cited by 12 · see citing works
“Although eukaryotes possess multiple SNF2 translocases, the division of labour between them is poorly understand, and even less is known about how their activities are coordinated (Poole and Cortez, 2017; Rickman and Smogorzewska, 2019).”
BackgroundHomologous recombination defects and how they affect replication fork maintenance
Son, M. Y., & Hasty, P. (2018) · Global Medical Genetics · doi:10.3934/genet.2018.4.192 · Cited by 12 · see citing works
“MMS22L directly interacts with RAD51 to stimulate RAD51-ssDNA filament formation and RAD51-dependent strand exchange activity, but limits RAD51 assembly onto dsDNA [52].”
BackgroundThe Role of the TSK/TONSL-H3.1 Pathway in Maintaining Genome Stability in Multicellular Eukaryotes
Huang, Y.-C., Yuan, W., & Jacob, Y. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23169029 · Cited by 12 · see citing works
“In vitro and in vivo experiments suggested that TONSL can rescue perturbed replication forks via two different mechanisms relying on RAD51: replication fork reversal and the homologous recombination-mediated repair of dsDNA breaks [80].”
BackgroundInfluentialTu, J., Yu, S., Li, J., Ren, M., Zhang, Y., Luo, J., Sun, K., Lv, Y., Han, Y., Huang, Y., et al. (2022) · Development · doi:10.1242/dev.200450 · Cited by 11 · see citing works
Stm1 regulates Ifh1 activity revealing crosstalk between ribosome biogenesis and ribosome dormancy
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“BRIP1 and FANCM), all better suited for the efficient repair of bulky lesions and highly toxic DSBs and crosslinks (Cantor et al., 2001; Li and Jin, 2012; Niraj et al., 2019; Piwko et al., 2016; Satoh and Hanawalt, 1996; Westermark et al., 2003).”
TFIP11 promotes replication fork reversal to preserve genome stability
Chen, J., Wu, M., Yang, Y., Ruan, C., Luo, Y., Song, L., Wu, T., Huang, J., Yang, B., & Liu, T. (2024) · Nature Communications · doi:10.1038/s41467-024-45684-3 · Cited by 8 · see citing works
A novel long non-coding RNA TONSL-AS1 regulates progression of gastric cancer via activating TONSL
Wang, P., Yang, X., Zhao, L., Liu, D., Liu, J., & Ding, Y.-B. (2019) · Experimental Cell Research · doi:10.1016/j.yexcr.2019.05.034 · Cited by 8 · see citing works
Chromatin dynamics and DNA replication roadblocks
Hammond-Martel, I., Verreault, A., & Würtele, H. (2021) · DNA repair · doi:10.1016/j.dnarep.2021.103140 · Cited by 8 · see citing works
Exploration of the hub genes and miRNAs in lung adenocarcinoma
Zhai, Y., Chen, Y., Li, Q., & Zhang, L.-Q. (2019) · Oncology Letters · doi:10.3892/ol.2019.10478 · Cited by 7 · see citing works
“The study by Piwko et al (29) examined the role of MMS22L‐TONSL in DNA recombination.”
BackgroundIntegrative pan-cancer landscape of MMS22L and its potential role in hepatocellular carcinoma
Guo, Z., Liu, F., & Gong, Q. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.1025970 · Cited by 5 · see citing works
“Previous studies have speculated that MMS22L mutations caused genomic instability and promoted certain types of ovarian and breast cancer (Piwko et al., 2016); however, our data suggested that patients with MMS22L mutations had a better prognosis than patients with wild-type MMS22L in UCEC.”
BackgroundMaize ZmDLR2/BRU1 Is Required for Lateral Root Primordium Emergence by Participating in DNA Repair
Li, D., Wang, Y., Li, Y., Wang, W., Wang, C., Wang, X., Zhou, W., Zhou, Y., Lian, X., Li, T., et al. (2025) · Plant Cell & Environment · doi:10.1111/pce.70037 · Cited by 4 · see citing works
“Further studies revealed that while the TONSL – MMS22L complex localises to unperturbed replication forks, it accumulates at collapsed forks with resected DNA (Piwko et al. 2016).”
InfluentialJia, M., Lin, L., Yu, H., Dong, Z., Pan, X., & Song, X. (2025) · Scientific Reports · doi:10.1038/s41598-025-85900-8 · Cited by 3 · see citing works
“Interactions with MMS22L and histone chaperones like ASF1 and CAF-1 facilitate this stress response, protecting adrenal cells from damage 34,35 .”
Replication stress promotes cellular transformation in Drosophila epithelium
Molano-Fernández, M., Hickson, I. D., & Herranz, H. (2025) · Cell Death Discovery · doi:10.1038/s41420-025-02383-2 · Cited by 2 · see citing works
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“Among these, the MMS22 like ( MMS22L ) gene, which encodes a protein involved in DNA repair mechanisms, has gained attention for its role in maintaining genomic integrity during and following high-intensity physical activity [307].”
TONSL promotes lung adenocarcinoma progression, immune escape and drug sensitivity
Liang, A., Wu, Z., Zhuo, T., Zhu, Y., Li, Z., Chen, S., Dai, L., Wang, Y., Tan, X., & Chen, M. (2024) · Clinical & Translational Oncology · doi:10.1007/s12094-024-03627-w · Cited by 2 · see citing works
“HoR-mediated DSB repair is facilitated by the formation of the MMS22L-TONSL complex, which is localized and recruited to the replication fork during DSBs and specifically modulates the activity of RAD51 in uncoupled replication forks [22].”
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“2e) is therefore biologically consistent with impaired DNA repair, as rescue of these defects requires functional TONSL protein [28, 29].”
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“The complex localizes to replication forks and DNA damage sites, where it binds to RPA-coated single-stranded DNA, and facilitates Rad51 mediated DNA strand exchange promoting homologous recombination-mediated fork restart ( 7 ).”
- Authors
- Piwko, W., Mlejnkova, L. J., Mutreja, K., Ranjha, L., Stafa, D., Smirnov, A., Brodersen, M. M., Zellweger, R., Sturzenegger, A., Janscak, P., Lopes, M., Peter, M., & Cejka, P.
- Affiliations
- ETH Zurich (CH)
- University of Zurich (CH)
- Corresponding author
- Piwko, Wojciech
- Peter, Matthias
- ORCID
- Venue
- The EMBO Journal
- Published
- 2016-10-26
- Volume
- 35
- Issue
- 23
- Pages
- 2584-2601
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC5283591
- OpenAlex
- W2542071790
- Cited by
- 87
- References
- 47
- Citations by year
- 2026: 4 · 2025: 13 · 2024: 8 · 2023: 7 · 2022: 10 · 2021: 14 · 2020: 4 · 2019: 8 · 2018: 13 · 2017: 6
- FWCI
- 4.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Research Council (268930, 617102)
- Swiss National Science Foundation (PP00P3_159323/1, PDFMP3 141759, 31003A_166451, 310030B_169312/1, 31003A_146924)
- ETH Zurich (0‐20854‐12)
- Krebsliga Schweiz (KFS‐3498‐08‐2014)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Keywords
- RAD51, homologous recombination, replication stress, replication fork restart, replication fork reversal, replication protein A, single-stranded DNA, DNA strand exchange, DNA double-strand break repair, replication fork recovery, histone modifications
- MeSH terms
- DNA Damage, DNA Repair, DNA Replication, DNA-Binding Proteins, HeLa Cells, Humans, Nuclear Proteins, Recombination, Genetic, NF-kappa B, Protein Interaction Mapping, Rad51 Recombinase, Protein Multimerization
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