Key mediators of somatic ATR signaling localize to unpaired chromosomes in spermatocytes

Fedoriw, Andrew; Menon, Debashish U.; Kim, Yuna; Mu, Weipeng; Magnuson, Terry

doi:10.1242/dev.126078

Cited by 16 publications

(19 citation statements)

References 36 publications

(49 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ATR phosphorylates multiple proteins involved in DNA repair, cell cycle control or replication origin firing 3 . Some of these are phosphorylated in the sex body, although it is not clear if they have any MSCI function, like phosphorylation of RPA32 on S33 (pRPA) or phosphorylation of CHK1 on S317 (pCHK1) 18 . Both markers were altered in Seckel mouse cells.…”

Section: Resultsmentioning

confidence: 99%

ATR is required to complete meiotic recombination in mice

Pacheco¹,

Maldonado-Linares²,

Marcet-Ortega³

et al. 2018

Nat Commun

View full text Add to dashboard Cite

Precise execution of recombination during meiosis is essential for forming chromosomally-balanced gametes. Meiotic recombination initiates with the formation and resection of DNA double-strand breaks (DSBs). Cellular responses to meiotic DSBs are critical for efficient repair and quality control, but molecular features of these remain poorly understood, particularly in mammals. Here we report that the DNA damage response protein kinase ATR is crucial for meiotic recombination and completion of meiotic prophase in mice. Using a hypomorphic Atr mutation and pharmacological inhibition of ATR in vivo and in cultured spermatocytes, we show that ATR, through its effector kinase CHK1, promotes efficient RAD51 and DMC1 assembly at RPA-coated resected DSB sites and establishment of interhomolog connections during meiosis. Furthermore, our findings suggest that ATR promotes local accumulation of recombination markers on unsynapsed axes during meiotic prophase to favor homologous chromosome synapsis. These data reveal that ATR plays multiple roles in mammalian meiotic recombination.

show abstract

Section: Resultsmentioning

confidence: 99%

ATR is required to complete meiotic recombination in mice

Pacheco¹,

Maldonado-Linares²,

Marcet-Ortega³

et al. 2018

Nat Commun

View full text Add to dashboard Cite

show abstract

“…It has been suggested that ATR phosphorylates RAD51 65 . ATR also phosphorylates CHK1 during meiosis 66 , and CHK1 in turn promotes RAD51 loading at DSBs 67 . A nonexclusive alternative is that focus numbers are reduced in the mutant because ATR slows their turnover, for example by inhibiting use of the sister chromatid as a recombination partner 5 , 68 .…”

Section: Discussionmentioning

confidence: 99%

ATR is a multifunctional regulator of male mouse meiosis

et al. 2018

View full text Add to dashboard Cite

Meiotic cells undergo genetic exchange between homologs through programmed DNA double-strand break (DSB) formation, recombination and synapsis. In mice, the DNA damage-regulated phosphatidylinositol-3-kinase-like kinase (PIKK) ATM regulates all of these processes. However, the meiotic functions of the PIKK ATR have remained elusive, because germline-specific depletion of this kinase is challenging. Here we uncover roles for ATR in male mouse prophase I progression. ATR deletion causes chromosome axis fragmentation and germ cell elimination at mid pachynema. This elimination cannot be rescued by deletion of ATM and the third DNA damage-regulated PIKK, PRKDC, consistent with the existence of a PIKK-independent surveillance mechanism in the mammalian germline. ATR is required for synapsis, in a manner genetically dissociable from DSB formation. ATR also regulates loading of recombinases RAD51 and DMC1 to DSBs and recombination focus dynamics on synapsed and asynapsed chromosomes. Our studies reveal ATR as a critical regulator of mouse meiosis.

show abstract

“…We have not seen the spread of the ATR signal into the surrounding chromatin. In contrast, in mice ATR is immunostained along the asynaptic elements with a less intense signal extending into the surrounding chromatin ( Turner et al 2004 ; Manterola et al 2009; Fedoriw et al 2015 ) and in the mole vole an intense ATR signal surrounds the entire sex bivalent ( Matveevsky et al 2016 ). SUMO-1 covers the asynaptic region as an extensive cloud in mice (La Salle et al 2008; Manterola et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Dual mechanism of chromatin remodeling in the common shrew sex trivalent (XY 1Y 2)

Matveevsky

Pavlova

Atsaeva

et al. 2017

CCG

View full text Add to dashboard Cite

Here we focus on the XY1Y2 condition in male common shrew Sorex araneus Linnaeus, 1758, applying electron microscopy and immunocytochemistry for a comprehensive analysis of structure, synapsis and behaviour of the sex trivalent in pachytene spermatocytes. The pachytene sex trivalent consists of three distinct parts: short and long synaptic SC fragments (between the X and Y1 and between the X and Y2, respectively) and a long asynaptic region of the X in-between. Chromatin inactivation was revealed in the XY1 synaptic region, the asynaptic region of the X and a very small asynaptic part of the Y2. This inactive part of the sex trivalent, that we named the ‘head’, forms a typical sex body and is located at the periphery of the meiotic nucleus at mid pachytene. The second part or ‘tail’, a long region of synapsis between the X and Y2 chromosomes, is directed from the periphery into the nucleus. Based on the distribution patterns of four proteins involved in chromatin inactivation, we propose a model of meiotic silencing in shrew sex chromosomes. Thus, we conclude that pachytene sex chromosomes are structurally and functionally two different chromatin domains with specific nuclear topology: the peripheral inactivated ‘true’ sex chromosome regions (part of the X and the Y1) and more centrally located transcriptionally active autosomal segments (part of the X and the Y2).

show abstract

Key mediators of somatic ATR signaling localize to unpaired chromosomes in spermatocytes

Cited by 16 publications

References 36 publications

ATR is required to complete meiotic recombination in mice

ATR is required to complete meiotic recombination in mice

ATR is a multifunctional regulator of male mouse meiosis

Dual mechanism of chromatin remodeling in the common shrew sex trivalent (XY 1Y 2)

Contact Info

Product

Resources

About