The MMS22L-TONSL complex mediates recovery from replication stress and homologous recombination

Lara O'Donnell; Stephanie Panier; Jan Wildenhain; Johnny M. Tkach; Abdallah Al-Hakim; Marie Claude Landry; Cristina Escribano-Diaz; Rachel K. Szilard; Jordan T.F. Young; Meagan Munro; Marella D. Canny; Nadine K. Kolas; Wei Zhang; Shane M. Harding; Jarkko Ylanko; Megan Mendez; Michael Mullin; Thomas Sun; Bianca Habermann; Alessandro Datti; Robert G. Bristow; Anne Claude Gingras; Michael D. Tyers; Grant W. Brown; Daniel Durocher

doi:10.1016/j.molcel.2010.10.024

The MMS22L-TONSL complex mediates recovery from replication stress and homologous recombination

Lara O'Donnell, Stephanie Panier, Jan Wildenhain, Johnny M. Tkach, Abdallah Al-Hakim, Marie Claude Landry, Cristina Escribano-Diaz, Rachel K. Szilard, Jordan T.F. Young, Meagan Munro, Marella D. Canny, Nadine K. Kolas, Wei Zhang, Shane M. Harding, Jarkko Ylanko, Megan Mendez, Michael Mullin, Thomas Sun, Bianca Habermann, Alessandro DattiRobert G. Bristow, Anne Claude Gingras, Michael D. Tyers, Grant W. Brown, Daniel Durocher^*

^*Corresponding author for this work

Division of Cancer Sciences (L5)

Research output: Contribution to journal › Article › peer-review

Abstract

Genome integrity is jeopardized each time DNA replication forks stall or collapse. Here we report the identification of a complex composed of MMS22L (C6ORF167) and TONSL (NFKBIL2) that participates in the recovery from replication stress. MMS22L and TONSL are homologous to yeast Mms22 and plant Tonsoku/Brushy1, respectively. MMS22L-TONSL accumulates at regions of ssDNA associated with distressed replication forks or at processed DNA breaks, and its depletion results in high levels of endogenous DNA double-strand breaks caused by an inability to complete DNA synthesis after replication fork collapse. Moreover, cells depleted of MMS22L are highly sensitive to camptothecin, a topoisomerase I poison that impairs DNA replication progression. Finally, MMS22L and TONSL are necessary for the efficient formation of RAD51 foci after DNA damage, and their depletion impairs homologous recombination. These results indicate that MMS22L and TONSL are genome caretakers that stimulate the recombination-dependent repair of stalled or collapsed replication forks.

Original language	English
Pages (from-to)	619-631
Number of pages	13
Journal	Molecular Cell
Volume	40
Issue number	4
DOIs	https://doi.org/10.1016/j.molcel.2010.10.024
Publication status	Published - 24 Nov 2010

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

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10.1016/j.molcel.2010.10.024

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O'Donnell, L., Panier, S., Wildenhain, J., Tkach, J. M., Al-Hakim, A., Landry, M. C., Escribano-Diaz, C., Szilard, R. K., Young, J. T. F., Munro, M., Canny, M. D., Kolas, N. K., Zhang, W., Harding, S. M., Ylanko, J., Mendez, M., Mullin, M., Sun, T., Habermann, B., ... Durocher, D. (2010). The MMS22L-TONSL complex mediates recovery from replication stress and homologous recombination. Molecular Cell, 40(4), 619-631. https://doi.org/10.1016/j.molcel.2010.10.024

@article{853e1ff6f9504d48855cd93539678c28,

title = "The MMS22L-TONSL complex mediates recovery from replication stress and homologous recombination",

abstract = "Genome integrity is jeopardized each time DNA replication forks stall or collapse. Here we report the identification of a complex composed of MMS22L (C6ORF167) and TONSL (NFKBIL2) that participates in the recovery from replication stress. MMS22L and TONSL are homologous to yeast Mms22 and plant Tonsoku/Brushy1, respectively. MMS22L-TONSL accumulates at regions of ssDNA associated with distressed replication forks or at processed DNA breaks, and its depletion results in high levels of endogenous DNA double-strand breaks caused by an inability to complete DNA synthesis after replication fork collapse. Moreover, cells depleted of MMS22L are highly sensitive to camptothecin, a topoisomerase I poison that impairs DNA replication progression. Finally, MMS22L and TONSL are necessary for the efficient formation of RAD51 foci after DNA damage, and their depletion impairs homologous recombination. These results indicate that MMS22L and TONSL are genome caretakers that stimulate the recombination-dependent repair of stalled or collapsed replication forks.",

author = "Lara O'Donnell and Stephanie Panier and Jan Wildenhain and Tkach, {Johnny M.} and Abdallah Al-Hakim and Landry, {Marie Claude} and Cristina Escribano-Diaz and Szilard, {Rachel K.} and Young, {Jordan T.F.} and Meagan Munro and Canny, {Marella D.} and Kolas, {Nadine K.} and Wei Zhang and Harding, {Shane M.} and Jarkko Ylanko and Megan Mendez and Michael Mullin and Thomas Sun and Bianca Habermann and Alessandro Datti and Bristow, {Robert G.} and Gingras, {Anne Claude} and Tyers, {Michael D.} and Brown, {Grant W.} and Daniel Durocher",

year = "2010",

month = nov,

day = "24",

doi = "10.1016/j.molcel.2010.10.024",

language = "English",

volume = "40",

pages = "619--631",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

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O'Donnell, L, Panier, S, Wildenhain, J, Tkach, JM, Al-Hakim, A, Landry, MC, Escribano-Diaz, C, Szilard, RK, Young, JTF, Munro, M, Canny, MD, Kolas, NK, Zhang, W, Harding, SM, Ylanko, J, Mendez, M, Mullin, M, Sun, T, Habermann, B, Datti, A, Bristow, RG, Gingras, AC, Tyers, MD, Brown, GW & Durocher, D 2010, 'The MMS22L-TONSL complex mediates recovery from replication stress and homologous recombination', Molecular Cell, vol. 40, no. 4, pp. 619-631. https://doi.org/10.1016/j.molcel.2010.10.024

TY - JOUR

T1 - The MMS22L-TONSL complex mediates recovery from replication stress and homologous recombination

AU - O'Donnell, Lara

AU - Panier, Stephanie

AU - Wildenhain, Jan

AU - Tkach, Johnny M.

AU - Al-Hakim, Abdallah

AU - Landry, Marie Claude

AU - Escribano-Diaz, Cristina

AU - Szilard, Rachel K.

AU - Young, Jordan T.F.

AU - Munro, Meagan

AU - Canny, Marella D.

AU - Kolas, Nadine K.

AU - Zhang, Wei

AU - Harding, Shane M.

AU - Ylanko, Jarkko

AU - Mendez, Megan

AU - Mullin, Michael

AU - Sun, Thomas

AU - Habermann, Bianca

AU - Datti, Alessandro

AU - Bristow, Robert G.

AU - Gingras, Anne Claude

AU - Tyers, Michael D.

AU - Brown, Grant W.

AU - Durocher, Daniel

PY - 2010/11/24

Y1 - 2010/11/24

N2 - Genome integrity is jeopardized each time DNA replication forks stall or collapse. Here we report the identification of a complex composed of MMS22L (C6ORF167) and TONSL (NFKBIL2) that participates in the recovery from replication stress. MMS22L and TONSL are homologous to yeast Mms22 and plant Tonsoku/Brushy1, respectively. MMS22L-TONSL accumulates at regions of ssDNA associated with distressed replication forks or at processed DNA breaks, and its depletion results in high levels of endogenous DNA double-strand breaks caused by an inability to complete DNA synthesis after replication fork collapse. Moreover, cells depleted of MMS22L are highly sensitive to camptothecin, a topoisomerase I poison that impairs DNA replication progression. Finally, MMS22L and TONSL are necessary for the efficient formation of RAD51 foci after DNA damage, and their depletion impairs homologous recombination. These results indicate that MMS22L and TONSL are genome caretakers that stimulate the recombination-dependent repair of stalled or collapsed replication forks.

AB - Genome integrity is jeopardized each time DNA replication forks stall or collapse. Here we report the identification of a complex composed of MMS22L (C6ORF167) and TONSL (NFKBIL2) that participates in the recovery from replication stress. MMS22L and TONSL are homologous to yeast Mms22 and plant Tonsoku/Brushy1, respectively. MMS22L-TONSL accumulates at regions of ssDNA associated with distressed replication forks or at processed DNA breaks, and its depletion results in high levels of endogenous DNA double-strand breaks caused by an inability to complete DNA synthesis after replication fork collapse. Moreover, cells depleted of MMS22L are highly sensitive to camptothecin, a topoisomerase I poison that impairs DNA replication progression. Finally, MMS22L and TONSL are necessary for the efficient formation of RAD51 foci after DNA damage, and their depletion impairs homologous recombination. These results indicate that MMS22L and TONSL are genome caretakers that stimulate the recombination-dependent repair of stalled or collapsed replication forks.

UR - http://www.scopus.com/inward/record.url?scp=78649326442&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2010.10.024

DO - 10.1016/j.molcel.2010.10.024

M3 - Article

C2 - 21055983

AN - SCOPUS:78649326442

SN - 1097-2765

VL - 40

SP - 619

EP - 631

JO - Molecular Cell

JF - Molecular Cell

IS - 4

ER -

The MMS22L-TONSL complex mediates recovery from replication stress and homologous recombination

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