Role of the <i>Saccharomyces cerevisiae</i> Rad53 Checkpoint Kinase in Signaling Double-Strand Breaks during the Meiotic Cell Cycle

Cartagena‐Lirola, Hugo; Guerini, Ilaria; Manfrini, Nicola; Lucchini, Giovanna; Longhese, Maria Pia

doi:10.1128/mcb.00375-08

Cited by 54 publications

(74 citation statements)

References 55 publications

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“…Mek1 specifically disappear in pachynema (Cartagena-Lirola et al 2008;Fukuda et al 2012;Cheng et al 2013). In C. elegans, exogenous DSBs can trigger nuclear reorganization and persistent SUN-1 phosphorylation in leptonema/zygonema but not in pachynema .…”

Section: Meiotic Checkpoint Networkmentioning

confidence: 99%

The Meiotic Checkpoint Network: Step-by-Step through Meiotic Prophase

Subramanian

Hochwagen

2014

Cold Spring Harbor Perspectives in Biology

174

178

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The generation of haploid gametes by meiosis is a highly conserved process for sexually reproducing organisms that, in almost all cases, involves the extensive breakage of chromosomes. These chromosome breaks occur during meiotic prophase and are essential for meiotic recombination as well as the subsequent segregation of homologous chromosomes. However, their formation and repair must be carefully monitored and choreographed with nuclear dynamics and the cell division program to avoid the creation of aberrant chromosomes and defective gametes. It is becoming increasingly clear that an intricate checkpointsignaling network related to the canonical DNA damage response is deeply interwoven with the meiotic program and preserves order during meiotic prophase. This meiotic checkpoint network (MCN) creates a wide range of dependent relationships controlling chromosome movement, chromosome pairing, chromatin structure, and double-strand break (DSB) repair. In this review, we summarize our current understanding of the MCN. We discuss commonalities and differences in different experimental systems, with a particular emphasis on the emerging design principles that control and limit cross talk between signals to ultimately ensure the faithful inheritance of chromosomes by the next generation.

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Section: Meiotic Checkpoint Networkmentioning

confidence: 99%

The Meiotic Checkpoint Network: Step-by-Step through Meiotic Prophase

Subramanian

Hochwagen

2014

Cold Spring Harbor Perspectives in Biology

174

178

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“…The archetypal mediator for checkpoint signaling is the conserved protein TopBP1 (in humans, Dpb11 in S. cerevisiae, and Cut5/Rad4 in Schizosaccharomyces pombe), which physically interacts with 9-1-1 via its Ddc1 subunit (8,9). Notably, however, Dpb11-dependent signaling via (S. cerevisiae) Rad9 and Rad53 does not seem to play a major role in the checkpoint response to programmed Spo11-induced meiotic DSBs (10)(11)(12)(13)(14), raising the question of how 9-1-1 transduces meiotic DSB-induced checkpoint signaling in meiosis.…”

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confidence: 99%

Synaptonemal complex formation and meiotic checkpoint signaling are linked to the lateral element protein Red1

Eichinger

Jentsch

2010

Proc. Natl. Acad. Sci. U.S.A.

100

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Meiosis generates four haploid daughters from a diploid parental cell. Central steps of meiosis are the pairing and recombination of homologous chromosomes followed by their segregation in two rounds of cell division. Meiotic recombination is monitored by a specialized DNA damage checkpoint pathway and is guided by a unique chromosomal structure called synaptonemal complex (SC), but how these events are coordinated is unclear. Here, we identify the SC protein Red1 as a crucial regulator of early meiosis. Red1 interacts with two subunits of the 9-1-1 checkpoint complex via two distinct 9-1-1 subunit-specific motifs. Association of 9-1-1 with Red1 is essential not only for meiotic checkpoint activation but for SC formation. Moreover, Red1 becomes SUMO-modified, which fosters interaction of Red1 with the central SC element Zip1, thereby securing timely SC formation. Thus, Red1, in addition to its structural role in the SC, is a crucial coordinator of meiosis by coupling checkpoint signaling to SC formation.checkpoint | meiosis | SUMO T he central activity of meiosis is the equal distribution of the genetic material of a diploid cell into four daughter cells. A key step of meiosis occurs in pachytene, in which the homologous chromosomes (i.e., the parental chromosomes, each containing two sister chromatids) align (synapsis). This alignment facilitates the exchange of parental information by homologous recombination and is crucial for chromosome segregation during the first meiotic division.The juxtaposition of the homologs in pachytene involves a unique chromosome structure known as the synaptonemal complex (SC), which assembles along the entire length of the bundled chromosomes (1, 2). The SC-induced arrangement of chromosomes appears to favor genetic exchange between homologs rather than sister chromatids. SC formation starts along each pair of homologous sister chromatids with the assembly of 50-nm-thick fibers, termed axial elements, which later become the so-called "lateral elements" of the SC. The axial elementcoated parental homologs finally associate via components of the central element, which zip the axial elements together, forming the SC. In Saccharomyces cerevisiae, the proteins Hop1 and Red1 are structural components of the lateral element, whereas the coiled-coil protein Zip1, which homo (oligo)-dimerizes during SC formation, forms the "steps" of the ladder-like central region. SC "zipping" is thought to take place by serial Zip1-Red1 interactions along the entire SC axis (1, 2).Early meiosis is under the control of the meiotic recombination checkpoint (called the meiotic checkpoint here; it is also known as the pachytene checkpoint), which prevents meiotic progression in the presence of unrepaired recombination intermediates. A key element of the meiotic surveillance pathway is the ring-shaped, heterotrimeric 9-1-1 complex (the proteins Rad9, Hus1, and Rad1 in mammals; the proteins Ddc1, Mec3, and Rad17 in S. cerevisiae), which is structurally related to the homotrimeric DNA-encircling DNA polymerase...

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“…Hop1-T318 phosphorylation is further critical for chromosomal recruitment and activation of Mek1 (31,32), a meiosisspecific protein kinase that upholds interhomolog bias (33)(34)(35)(36)(37)(38). Mec1 and Tel1 also phosphorylate SQ and TQ sites in several other phosphoproteins during meiosis, including histone H2A at S129 (H2A-S129 [␥H2A]), Rad53, RPA, Sae2, and Zip1 (39)(40)(41)(42)(43). The Mec1/Tel1-dependent phosphorylation of Zip1 (32,42) dynamically destabilizes homology-independent centromere pairing in response to DSBs (42).…”

mentioning

confidence: 99%

Three Distinct Modes of Mec1/ATR and Tel1/ATM Activation Illustrate Differential Checkpoint Targeting during Budding Yeast Early Meiosis

Cheng

Chuang

Shen

et al. 2013

Molecular and Cellular Biology

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bRecombination and synapsis of homologous chromosomes are hallmarks of meiosis in many organisms. Meiotic recombination is initiated by Spo11-induced DNA double-strand breaks (DSBs), whereas chromosome synapsis is mediated by a tripartite structure named the synaptonemal complex (SC). Previously, we proposed that budding yeast SC is assembled via noncovalent interactions between the axial SC protein Red1, SUMO chains or conjugates, and the central SC protein Zip1. Incomplete synapsis and unrepaired DNA are monitored by Mec1/Tel1-dependent checkpoint responses that prevent exit from the pachytene stage. Here, our results distinguished three distinct modes of Mec1/Tec1 activation during early meiosis that led to phosphorylation of three targets, histone H2A at S129 (␥H2A), Hop1, and Zip1, which are involved, respectively, in DNA replication, the interhomolog recombination and chromosome synapsis checkpoint, and destabilization of homology-independent centromere pairing. ␥H2A phosphorylation is Red1 independent and occurs prior to Spo11-induced DSBs. DSB-and Red1-dependent Hop1 phosphorylation is activated via interaction of the Red1-SUMO chain/conjugate ensemble with the Ddc1-Rad17-Mec3 (9-1-1) checkpoint complex and the Mre11-Rad50-Xrs2 complex. During SC assembly, Zip1 outcompetes 9-1-1 from the Red1-SUMO chain ensemble to attenuate Hop1 phosphorylation. In contrast, chromosome synapsis cannot attenuate DSB-dependent and Red1-independent Zip1 phosphorylation. These results reveal how DNA replication, DSB repair, and chromosome synapsis are differentially monitored by the meiotic checkpoint network. Meiosis generates four haploid daughter cells from a diploid parental cell. The central steps of meiosis are the pairing and recombination of homologous chromosomes, followed by their segregation in two rounds of cell division. A key step of meiosis occurs in the pachytene stage, in which the homologous chromosomes (i.e., the parental chromosomes, each containing two sister chromatids) align (synapsis) (1, 2). Meiotic recombination is initiated by DNA double-strand breaks (DSBs) induced by Spo11, and chromosome synapsis is mediated by a tripartite structure named the synaptonemal complex (SC). The SC is a zipper-like protein complex that consists of a central element and two dense lateral/axial elements. The tripartite structure of the SC is strikingly conserved from budding yeast to humans, underscoring its prominent function during meiosis (2-4). In the budding yeast Saccharomyces cerevisiae, the central element of the SC includes a major component (Zip1) and the SC initiating proteins (Zip2-4, Mer3, Msh4-5, Spo16, and Ecm11-Gcm2) (5-15). The axial elements include the sister chromatid cohesin complex (Rec8/Scc3/ Smc1/Smc3) and three meiosis-specific components, Hop1, Red1, and Mek1 (1, 16, 17). Red1 and Hop1, like Rec8, assemble along the rod-like cores of meiotic chromosomes (16). The SC proteins have different impacts on meiotic DNA recombination and cell cycle progression. In cell cycle progression, checkpoint m...

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Role of the Saccharomyces cerevisiae Rad53 Checkpoint Kinase in Signaling Double-Strand Breaks during the Meiotic Cell Cycle

Cited by 54 publications

References 55 publications

The Meiotic Checkpoint Network: Step-by-Step through Meiotic Prophase

The Meiotic Checkpoint Network: Step-by-Step through Meiotic Prophase

Synaptonemal complex formation and meiotic checkpoint signaling are linked to the lateral element protein Red1

Three Distinct Modes of Mec1/ATR and Tel1/ATM Activation Illustrate Differential Checkpoint Targeting during Budding Yeast Early Meiosis

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