<i>Drosophila</i> ATM and ATR have distinct activities in the regulation of meiotic DNA damage and repair

Joyce, Eric F.; Pedersen, Michael; Tiong, Stanley; White-Brown, Sanese; Paul, Anshu; Campbell, Shelagh D.; McKim, Kim S.

doi:10.1083/jcb.201104121

Cited by 118 publications

(119 citation statements)

References 46 publications

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“…Interestingly, the frequency of ventralized embryos was reduced as compared to the spn-A single mutant. This is probably not due to a failure in responding to DSBs since the appearance of g-H2AV, which depends on Ataxia-Telangiectasia Mutated (ATM), is not affected (Joyce et al 2011). We also tested mutations in another precondition gene, rec, and found a similar suppression of checkpoint activity in spn-A mutants (Table 2).…”

Section: Repair Of Dsbs In Mei-218; Spn-d Depends On Ligase4mentioning

confidence: 89%

Multiple Barriers to Nonhomologous DNA End Joining During Meiosis inDrosophila

Joyce¹,

Paul

Chen

et al. 2012

Genetics

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Repair of meiotic double-strand breaks (DSBs) uses the homolog and recombination to yield crossovers while alternative pathways such as nonhomologous end joining (NHEJ) are suppressed. Our results indicate that NHEJ is blocked at two steps of DSB repair during meiotic prophase: first by the activity of the MCM-like protein MEI-218, which is required for crossover formation, and, second, by Rad51-related proteins SPN-B (XRCC3) and SPN-D (RAD51C), which physically interact and promote homologous recombination (HR). We further show that the MCM-like proteins also promote the activity of the DSB repair checkpoint pathway, indicating an early requirement for these proteins in DSB processing. We propose that when a meiotic DSB is formed in the absence of both MEI-218 and SPN-B or SPN-D, a DSB substrate is generated that can enter the NHEJ repair pathway. Indeed, due to its high error rate, multiple barriers may have evolved to prevent NHEJ activity during meiosis.

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Section: Repair Of Dsbs In Mei-218; Spn-d Depends On Ligase4mentioning

confidence: 89%

Multiple Barriers to Nonhomologous DNA End Joining During Meiosis inDrosophila

Joyce¹,

Paul

Chen

et al. 2012

Genetics

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“…The negative regulation of synapsis on DSB activity has also been directly detected in S. cerevisiae (Thacker et al, 2014). HORMAD1 is phosphorylated (Kogo et al, 2012;Shin et al, 2010;Wojtasz et al, 2009) and could be a target of the ATM kinase, which has been proposed to play a role in the downregulation of DSB formation in Drosophila and mice, based on the detection of increased DSB levels in Atm mutants (Joyce et al, 2011;Lange et al, 2011).…”

Section: Discussion Association Of Mei4 With Chromosome Axesmentioning

confidence: 99%

MEI4: a central player in the regulation of meiotic DNA double strand break formation in the mouse

Kumar

Ghyselinck

Ishiguro

et al. 2015

Journal of Cell Science

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The formation of programmed DNA double-strand breaks (DSBs) at the beginning of meiotic prophase marks the initiation of meiotic recombination. Meiotic DSB formation is catalyzed by SPO11 and their repair takes place on meiotic chromosome axes. The evolutionarily conserved MEI4 protein is required for meiotic DSB formation and is localized on chromosome axes. Here, we show that HORMAD1, one of the meiotic chromosome axis components, is required for MEI4 localization. Importantly, the quantitative correlation between the level of axis-associated MEI4 and DSB formation suggests that axis-associated MEI4 could be a limiting factor for DSB formation. We also show that MEI1, REC8 and RAD21L are important for proper MEI4 localization. These findings on MEI4 dynamics during meiotic prophase suggest that the association of MEI4 to chromosome axes is required for DSB formation, and that the loss of this association upon DSB repair could contribute to turning off meiotic DSB formation.

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“…Third, Mei-41 is dispensable for normal GSC maintenance, but it protects GSCs in the presence of DNA damage. Although Lok and Mei-41 behave similarly in DNA-damage checkpoint control during meiosis and late germ cell development (Joyce et al, 2011;Klattenhoff et al, 2007), they behave in an opposite way in GSCs in response to DNA damage. Finally, Grp is dispensable for GSC self-renewal in the absence and presence of DNA damage.…”

Section: Discussionmentioning

confidence: 99%

“…In various cell types, ATM-CHK2 and ATR-CHK1 kinase pathways are responsible for DNA damage-induced checkpoint activation (Callegari and Kelly, 2007;Kastan and Bartek, 2004;Sperka et al, 2012). During Drosophila meiosis, Mei-41, but not Tefu, is required for checkpoint activity, indicating that Tefu and Mei-41 could have different functions in germ cells (Joyce et al, 2011). Both Mei-41 and Lok have been shown to be required for DNA damage-evoked checkpoint control in Drosophila germ cells and embryonic cells (Abdu et al, 2002;Chen et al, 2007;Klattenhoff et al, 2007;Masrouha et al, 2003), and Grp can control the entry into the anaphase of cell cycle in response to DNA damage, the G2-M checkpoint activation as well as the Drosophila midblastula transition (de Vries et al, 2005;Royou et al, 2005;Takada et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

DNA damage-induced Lok/CHK2 activation compromises germline stem cell self-renewal and lineage differentiation

Han

Song

et al. 2016

Development

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Stem cells in adult tissues are constantly exposed to genotoxic stress and also accumulate DNA damage with age. However, it remains largely unknown how DNA damage affects both stem cell selfrenewal and differentiation. In this study, we show that DNA damage retards germline stem cell (GSC) self-renewal and progeny differentiation in a Lok kinase-dependent manner in the Drosophila ovary. Both heatshock-inducible endonuclease I-CreI expression and X-ray irradiation can efficiently introduce double-strand breaks in GSCs and their progeny, resulting in a rapid GSC loss and a GSC progeny differentiation defect. Surprisingly, the elimination of Lok or its kinase activity can almost fully rescue the GSC loss and the progeny differentiation defect caused by DNA damage induced by I-CreI or X-ray. In addition, the reduction in bone morphogenetic protein signaling and Shotgun expression only makes a limited contribution to DNA damage-induced GSC loss. Finally, DNA damage also decreases the expression of the master differentiation factor Bam in a Lok-dependent manner, which helps explain the GSC progeny differentiation defect. Therefore, this study demonstrates, for the first time in vivo, that Lok kinase activation is required for the DNA damage-mediated disruption of adult stem cell self-renewal and lineage differentiation, and might also offer novel insight into how DNA damage causes tissue aging and cancer formation.

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Drosophila ATM and ATR have distinct activities in the regulation of meiotic DNA damage and repair

Abstract: ATM and ATR display distinct activities in meiotic DSB repair, such that ATM functions in DNA damage repair and negative feedback control over programmed double strand breaks, whereas ATR is required for checkpoint activity.

Cited by 118 publications

References 46 publications

Multiple Barriers to Nonhomologous DNA End Joining During Meiosis inDrosophila

Multiple Barriers to Nonhomologous DNA End Joining During Meiosis inDrosophila

MEI4: a central player in the regulation of meiotic DNA double strand break formation in the mouse

DNA damage-induced Lok/CHK2 activation compromises germline stem cell self-renewal and lineage differentiation

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