ATM/ATR kinases link the synaptonemal complex and DNA double-strand break repair pathway choice

Laura I. Láscarez-Lagunas; Saravanapriah Nadarajan; Marina Martinez-Garcia; Julianna N. Quinn; Elena Todisco; Tanuj Thakkar; Elizaveta Berson; Don Eaford; Oliver Crawley; Alex Montoya; Peter Faull; Nuria Ferrandiz; Consuelo Barroso; Sara Labella; Emily Koury; Sarit Smolikove; Monique Zetka; Enrique Martinez-Perez; Monica P. Colaiácovo

doi:10.1016/j.cub.2022.08.081

ATM/ATR kinases link the synaptonemal complex and DNA double-strand break repair pathway choice

Laura I. Láscarez-Lagunas, Saravanapriah Nadarajan, Marina Martinez-Garcia, Julianna N. Quinn, Elena Todisco, Tanuj Thakkar, Elizaveta Berson, Don Eaford, Oliver Crawley, Alex Montoya, Peter Faull, Nuria Ferrandiz, Consuelo Barroso, Sara Labella, Emily Koury, Sarit Smolikove, Monique Zetka, Enrique Martinez-Perez, Monica P. Colaiácovo^*

^*Corresponding author for this work

PCE - Proteomics Center of Excellence

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

7 Scopus citations

Abstract

DNA double-strand breaks (DSBs) are deleterious lesions, which must be repaired precisely to maintain genomic stability. During meiosis, programmed DSBs are repaired via homologous recombination (HR) while repair using the nonhomologous end joining (NHEJ) pathway is inhibited, thereby ensuring crossover formation and accurate chromosome segregation.^1,2 How DSB repair pathway choice is implemented during meiosis is unknown. In C. elegans, meiotic DSB repair takes place in the context of the fully formed, highly dynamic zipper-like structure present between homologous chromosomes called the synaptonemal complex (SC).^{3,4,5,6,7,8,9} The SC consists of a pair of lateral elements bridged by a central region composed of the SYP proteins in C. elegans. How the structural components of the SC are regulated to maintain the architectural integrity of the assembled SC around DSB repair sites remained unclear. Here, we show that SYP-4, a central region component of the SC, is phosphorylated at Serine 447 in a manner dependent on DSBs and the ATM/ATR DNA damage response kinases. We show that this SYP-4 phosphorylation is critical for preserving the SC structure following exogenous (γ-IR-induced) DSB formation and for promoting normal DSB repair progression and crossover patterning following SPO-11-dependent and exogenous DSBs. We propose a model in which ATM/ATR-dependent phosphorylation of SYP-4 at the S447 site plays important roles both in maintaining the architectural integrity of the SC following DSB formation and in warding off repair via the NHEJ repair pathway, thereby preventing aneuploidy.

Original language	English (US)
Pages (from-to)	4719-4726.e4
Journal	Current Biology
Volume	32
Issue number	21
DOIs	https://doi.org/10.1016/j.cub.2022.08.081
State	Published - Nov 7 2022

Funding

We are grateful to the Caenorhabditis Genetics Center for providing strains. We thank the members of the Colaiácovo lab for critical reading of this manuscript. This work was supported by CIHR grant 119468 to M.Z. a MRC core-funded grant to E.M.-P. and National Institutes of Health grant R01GM072551 to M.P.C. Conceptualization, L.I.L.-L. S.N. and M.P.C.; investigation, L.I.L.-L. S.N. M.M.-G. J.N.Q. E.T. T.T. E.B. D.E. A.M. O.C. and P.F.; resources, N.F. C.B. S.L. E.K. S.S. M.Z. and E.M.-P.; writing – original draft, L.I.L.-L. S.N. and M.P.C.; writing – review & editing, L.I.L.-L. S.N. M.P.C. S.S. M.Z. and E.M.-P.; supervision, M.P.C. S.S. M.Z. and E.M.-P.; funding acquisition, M.P.C. M.Z. and E.M.-P. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. We are grateful to the Caenorhabditis Genetics Center for providing strains. We thank the members of the Colaiácovo lab for critical reading of this manuscript. This work was supported by CIHR grant 119468 to M.Z., a MRC core-funded grant to E.M.-P., and National Institutes of Health grant R01GM072551 to M.P.C.

Keywords

ATM/ATR
C. elegans
CO patterning
DSB
NHEJ
SYP-4
meiosis
synaptonemal complex

ASJC Scopus subject areas

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Agricultural and Biological Sciences

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10.1016/j.cub.2022.08.081

Cite this

Láscarez-Lagunas, L. I., Nadarajan, S., Martinez-Garcia, M., Quinn, J. N., Todisco, E., Thakkar, T., Berson, E., Eaford, D., Crawley, O., Montoya, A., Faull, P., Ferrandiz, N., Barroso, C., Labella, S., Koury, E., Smolikove, S., Zetka, M., Martinez-Perez, E., & Colaiácovo, M. P. (2022). ATM/ATR kinases link the synaptonemal complex and DNA double-strand break repair pathway choice. Current Biology, 32(21), 4719-4726.e4. https://doi.org/10.1016/j.cub.2022.08.081

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abstract = "DNA double-strand breaks (DSBs) are deleterious lesions, which must be repaired precisely to maintain genomic stability. During meiosis, programmed DSBs are repaired via homologous recombination (HR) while repair using the nonhomologous end joining (NHEJ) pathway is inhibited, thereby ensuring crossover formation and accurate chromosome segregation.1,2 How DSB repair pathway choice is implemented during meiosis is unknown. In C. elegans, meiotic DSB repair takes place in the context of the fully formed, highly dynamic zipper-like structure present between homologous chromosomes called the synaptonemal complex (SC).3,4,5,6,7,8,9 The SC consists of a pair of lateral elements bridged by a central region composed of the SYP proteins in C. elegans. How the structural components of the SC are regulated to maintain the architectural integrity of the assembled SC around DSB repair sites remained unclear. Here, we show that SYP-4, a central region component of the SC, is phosphorylated at Serine 447 in a manner dependent on DSBs and the ATM/ATR DNA damage response kinases. We show that this SYP-4 phosphorylation is critical for preserving the SC structure following exogenous (γ-IR-induced) DSB formation and for promoting normal DSB repair progression and crossover patterning following SPO-11-dependent and exogenous DSBs. We propose a model in which ATM/ATR-dependent phosphorylation of SYP-4 at the S447 site plays important roles both in maintaining the architectural integrity of the SC following DSB formation and in warding off repair via the NHEJ repair pathway, thereby preventing aneuploidy.",

keywords = "ATM/ATR, C. elegans, CO patterning, DSB, NHEJ, SYP-4, meiosis, synaptonemal complex",

author = "L{\'a}scarez-Lagunas, {Laura I.} and Saravanapriah Nadarajan and Marina Martinez-Garcia and Quinn, {Julianna N.} and Elena Todisco and Tanuj Thakkar and Elizaveta Berson and Don Eaford and Oliver Crawley and Alex Montoya and Peter Faull and Nuria Ferrandiz and Consuelo Barroso and Sara Labella and Emily Koury and Sarit Smolikove and Monique Zetka and Enrique Martinez-Perez and Colai{\'a}covo, {Monica P.}",

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doi = "10.1016/j.cub.2022.08.081",

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Láscarez-Lagunas, LI, Nadarajan, S, Martinez-Garcia, M, Quinn, JN, Todisco, E, Thakkar, T, Berson, E, Eaford, D, Crawley, O, Montoya, A, Faull, P, Ferrandiz, N, Barroso, C, Labella, S, Koury, E, Smolikove, S, Zetka, M, Martinez-Perez, E & Colaiácovo, MP 2022, 'ATM/ATR kinases link the synaptonemal complex and DNA double-strand break repair pathway choice', Current Biology, vol. 32, no. 21, pp. 4719-4726.e4. https://doi.org/10.1016/j.cub.2022.08.081

TY - JOUR

T1 - ATM/ATR kinases link the synaptonemal complex and DNA double-strand break repair pathway choice

AU - Láscarez-Lagunas, Laura I.

AU - Nadarajan, Saravanapriah

AU - Martinez-Garcia, Marina

AU - Quinn, Julianna N.

AU - Todisco, Elena

AU - Thakkar, Tanuj

AU - Berson, Elizaveta

AU - Eaford, Don

AU - Crawley, Oliver

AU - Montoya, Alex

AU - Faull, Peter

AU - Ferrandiz, Nuria

AU - Barroso, Consuelo

AU - Labella, Sara

AU - Koury, Emily

AU - Smolikove, Sarit

AU - Zetka, Monique

AU - Martinez-Perez, Enrique

AU - Colaiácovo, Monica P.

PY - 2022/11/7

Y1 - 2022/11/7

N2 - DNA double-strand breaks (DSBs) are deleterious lesions, which must be repaired precisely to maintain genomic stability. During meiosis, programmed DSBs are repaired via homologous recombination (HR) while repair using the nonhomologous end joining (NHEJ) pathway is inhibited, thereby ensuring crossover formation and accurate chromosome segregation.1,2 How DSB repair pathway choice is implemented during meiosis is unknown. In C. elegans, meiotic DSB repair takes place in the context of the fully formed, highly dynamic zipper-like structure present between homologous chromosomes called the synaptonemal complex (SC).3,4,5,6,7,8,9 The SC consists of a pair of lateral elements bridged by a central region composed of the SYP proteins in C. elegans. How the structural components of the SC are regulated to maintain the architectural integrity of the assembled SC around DSB repair sites remained unclear. Here, we show that SYP-4, a central region component of the SC, is phosphorylated at Serine 447 in a manner dependent on DSBs and the ATM/ATR DNA damage response kinases. We show that this SYP-4 phosphorylation is critical for preserving the SC structure following exogenous (γ-IR-induced) DSB formation and for promoting normal DSB repair progression and crossover patterning following SPO-11-dependent and exogenous DSBs. We propose a model in which ATM/ATR-dependent phosphorylation of SYP-4 at the S447 site plays important roles both in maintaining the architectural integrity of the SC following DSB formation and in warding off repair via the NHEJ repair pathway, thereby preventing aneuploidy.

AB - DNA double-strand breaks (DSBs) are deleterious lesions, which must be repaired precisely to maintain genomic stability. During meiosis, programmed DSBs are repaired via homologous recombination (HR) while repair using the nonhomologous end joining (NHEJ) pathway is inhibited, thereby ensuring crossover formation and accurate chromosome segregation.1,2 How DSB repair pathway choice is implemented during meiosis is unknown. In C. elegans, meiotic DSB repair takes place in the context of the fully formed, highly dynamic zipper-like structure present between homologous chromosomes called the synaptonemal complex (SC).3,4,5,6,7,8,9 The SC consists of a pair of lateral elements bridged by a central region composed of the SYP proteins in C. elegans. How the structural components of the SC are regulated to maintain the architectural integrity of the assembled SC around DSB repair sites remained unclear. Here, we show that SYP-4, a central region component of the SC, is phosphorylated at Serine 447 in a manner dependent on DSBs and the ATM/ATR DNA damage response kinases. We show that this SYP-4 phosphorylation is critical for preserving the SC structure following exogenous (γ-IR-induced) DSB formation and for promoting normal DSB repair progression and crossover patterning following SPO-11-dependent and exogenous DSBs. We propose a model in which ATM/ATR-dependent phosphorylation of SYP-4 at the S447 site plays important roles both in maintaining the architectural integrity of the SC following DSB formation and in warding off repair via the NHEJ repair pathway, thereby preventing aneuploidy.

KW - ATM/ATR

KW - C. elegans

KW - CO patterning

KW - DSB

KW - NHEJ

KW - SYP-4

KW - meiosis

KW - synaptonemal complex

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SN - 0960-9822

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JF - Current Biology

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ER -

ATM/ATR kinases link the synaptonemal complex and DNA double-strand break repair pathway choice

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