Cargando…

Positive regulation of meiotic DNA double-strand break formation by activation of the DNA damage checkpoint kinase Mec1(ATR)

During meiosis, formation and repair of programmed DNA double-strand breaks (DSBs) create genetic exchange between homologous chromosomes—a process that is critical for reductional meiotic chromosome segregation and the production of genetically diverse sexually reproducing populations. Meiotic DSB...

Descripción completa

Detalles Bibliográficos
Autores principales: Gray, Stephen, Allison, Rachal M., Garcia, Valerie, Goldman, Alastair S. H., Neale, Matthew J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728922/
https://www.ncbi.nlm.nih.gov/pubmed/23902647
http://dx.doi.org/10.1098/rsob.130019
_version_ 1782278930746572800
author Gray, Stephen
Allison, Rachal M.
Garcia, Valerie
Goldman, Alastair S. H.
Neale, Matthew J.
author_facet Gray, Stephen
Allison, Rachal M.
Garcia, Valerie
Goldman, Alastair S. H.
Neale, Matthew J.
author_sort Gray, Stephen
collection PubMed
description During meiosis, formation and repair of programmed DNA double-strand breaks (DSBs) create genetic exchange between homologous chromosomes—a process that is critical for reductional meiotic chromosome segregation and the production of genetically diverse sexually reproducing populations. Meiotic DSB formation is a complex process, requiring numerous proteins, of which Spo11 is the evolutionarily conserved catalytic subunit. Precisely how Spo11 and its accessory proteins function or are regulated is unclear. Here, we use Saccharomyces cerevisiae to reveal that meiotic DSB formation is modulated by the Mec1(ATR) branch of the DNA damage signalling cascade, promoting DSB formation when Spo11-mediated catalysis is compromised. Activation of the positive feedback pathway correlates with the formation of single-stranded DNA (ssDNA) recombination intermediates and activation of the downstream kinase, Mek1. We show that the requirement for checkpoint activation can be rescued by prolonging meiotic prophase by deleting the NDT80 transcription factor, and that even transient prophase arrest caused by Ndt80 depletion is sufficient to restore meiotic spore viability in checkpoint mutants. Our observations are unexpected given recent reports that the complementary kinase pathway Tel1(ATM) acts to inhibit DSB formation. We propose that such antagonistic regulation of DSB formation by Mec1 and Tel1 creates a regulatory mechanism, where the absolute frequency of DSBs is maintained at a level optimal for genetic exchange and efficient chromosome segregation.
format Online
Article
Text
id pubmed-3728922
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher The Royal Society
record_format MEDLINE/PubMed
spelling pubmed-37289222013-08-06 Positive regulation of meiotic DNA double-strand break formation by activation of the DNA damage checkpoint kinase Mec1(ATR) Gray, Stephen Allison, Rachal M. Garcia, Valerie Goldman, Alastair S. H. Neale, Matthew J. Open Biol Research During meiosis, formation and repair of programmed DNA double-strand breaks (DSBs) create genetic exchange between homologous chromosomes—a process that is critical for reductional meiotic chromosome segregation and the production of genetically diverse sexually reproducing populations. Meiotic DSB formation is a complex process, requiring numerous proteins, of which Spo11 is the evolutionarily conserved catalytic subunit. Precisely how Spo11 and its accessory proteins function or are regulated is unclear. Here, we use Saccharomyces cerevisiae to reveal that meiotic DSB formation is modulated by the Mec1(ATR) branch of the DNA damage signalling cascade, promoting DSB formation when Spo11-mediated catalysis is compromised. Activation of the positive feedback pathway correlates with the formation of single-stranded DNA (ssDNA) recombination intermediates and activation of the downstream kinase, Mek1. We show that the requirement for checkpoint activation can be rescued by prolonging meiotic prophase by deleting the NDT80 transcription factor, and that even transient prophase arrest caused by Ndt80 depletion is sufficient to restore meiotic spore viability in checkpoint mutants. Our observations are unexpected given recent reports that the complementary kinase pathway Tel1(ATM) acts to inhibit DSB formation. We propose that such antagonistic regulation of DSB formation by Mec1 and Tel1 creates a regulatory mechanism, where the absolute frequency of DSBs is maintained at a level optimal for genetic exchange and efficient chromosome segregation. The Royal Society 2013-07 /pmc/articles/PMC3728922/ /pubmed/23902647 http://dx.doi.org/10.1098/rsob.130019 Text en http://creativecommons.org/licenses/by/3.0/ © 2013 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0/, which permits unrestricted use, provided the original author and source are credited.
spellingShingle Research
Gray, Stephen
Allison, Rachal M.
Garcia, Valerie
Goldman, Alastair S. H.
Neale, Matthew J.
Positive regulation of meiotic DNA double-strand break formation by activation of the DNA damage checkpoint kinase Mec1(ATR)
title Positive regulation of meiotic DNA double-strand break formation by activation of the DNA damage checkpoint kinase Mec1(ATR)
title_full Positive regulation of meiotic DNA double-strand break formation by activation of the DNA damage checkpoint kinase Mec1(ATR)
title_fullStr Positive regulation of meiotic DNA double-strand break formation by activation of the DNA damage checkpoint kinase Mec1(ATR)
title_full_unstemmed Positive regulation of meiotic DNA double-strand break formation by activation of the DNA damage checkpoint kinase Mec1(ATR)
title_short Positive regulation of meiotic DNA double-strand break formation by activation of the DNA damage checkpoint kinase Mec1(ATR)
title_sort positive regulation of meiotic dna double-strand break formation by activation of the dna damage checkpoint kinase mec1(atr)
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728922/
https://www.ncbi.nlm.nih.gov/pubmed/23902647
http://dx.doi.org/10.1098/rsob.130019
work_keys_str_mv AT graystephen positiveregulationofmeioticdnadoublestrandbreakformationbyactivationofthednadamagecheckpointkinasemec1atr
AT allisonrachalm positiveregulationofmeioticdnadoublestrandbreakformationbyactivationofthednadamagecheckpointkinasemec1atr
AT garciavalerie positiveregulationofmeioticdnadoublestrandbreakformationbyactivationofthednadamagecheckpointkinasemec1atr
AT goldmanalastairsh positiveregulationofmeioticdnadoublestrandbreakformationbyactivationofthednadamagecheckpointkinasemec1atr
AT nealematthewj positiveregulationofmeioticdnadoublestrandbreakformationbyactivationofthednadamagecheckpointkinasemec1atr