The MMS22L-TONSL complex mediates recovery from replication stress and homologous recombination.
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.
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
Lara
L
O'Donnell
Stephanie
S
Panier
Jan
J
Wildenhain
Johnny M
JM
Tkach
Abdallah
A
Al-Hakim
Marie-Claude
MC
Landry
Cristina
C
Escribano-Diaz
Rachel K
RK
Szilard
Jordan T F
JT
Young
Meagan
M
Munro
Marella D
MD
Canny
Nadine K
NK
Kolas
Wei
W
Zhang
Shane M
SM
Harding
Jarkko
J
Ylanko
Megan
M
Mendez
Michael
M
Mullin
Thomas
T
Sun
Bianca
B
Habermann
Alessandro
A
Datti
Robert G
RG
Bristow
Anne-Claude
AC
Gingras
Michael D
MD
Tyers
Grant W
GW
Brown
Daniel
D
Durocher
D002470:Cell Survival; D053903:DNA Breaks, Double-Stranded; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D046912:Multiprotein Complexes / Q000378:metabolism*; D016328:NF-kappa B / Q000737:chemistry / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D011995:Recombination, Genetic; D016196:S Phase; D013312:Stress, Physiological; D013698:Templates, Genetic
D004268:DNA-Binding Proteins; C554517:MMS22L protein, human; D046912:Multiprotein Complexes; D016328:NF-kappa B; D009687:Nuclear Proteins; C093394:TONSL protein, human