Prdm9 and Meiotic Cohesin Proteins Cooperatively Promote DNA Double-Strand Break Formation in Mammalian Spermatocytes

Bhattacharyya, Tanmoy; Walker, Michael; Powers, Natalie R.; Brunton, Catherine; Fine, Alexander D.; Petkov, Petko M.; Handel, Mary Ann

doi:10.1016/j.cub.2019.02.007

Cited by 40 publications

(28 citation statements)

References 69 publications

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“…MSCI is triggered by XY asynapsis in spermatocytes and is marked by sequestration of the sex chromosomes in the "sex body" (29). Spermatocytes undergoing PRDM9-deficient meiotic arrest in B6 mice do not form a normal sex body, as unsynapsed autosomes and unrepaired DSBs compromise recruitment of silencing factors to sex chromosomes (8,17,32). This could potentially lead to failure of MSCI, triggering meiotic arrest of PRDM9-deficient spermatocytes (8,32).…”

Section: Discussionmentioning

confidence: 99%

“…Homozygous B6.Prdm9 EP/EP males exhibited the expected meiotic arrest and infertility, phenocopying both the Prdm9-null condition (8) and a recently reported methyltransferase-dead Prdm9 allele (fig. S1G) (16,17). In contrast to the infertile males, all tested homozygous B6.Prdm9 EP/EP females produced at least one-and up to fivelitters when mated to B6 males over a period of 6 months (Fig.…”

Section: Sex-specific Requirement For Prdm9-dependent Histone Methyltmentioning

confidence: 95%

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Sexual dimorphism in the meiotic requirement for PRDM9: A mammalian evolutionary safeguard

et al. 2020

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In many mammals, genomic sites for recombination are determined by the histone methyltransferase PRMD9. Some mouse strains lacking PRDM9 are infertile, but instances of fertility or semifertility in the absence of PRDM9 have been reported in mice, canines, and a human female. Such findings raise the question of how the loss of PRDM9 is circumvented to maintain fertility. We show that genetic background and sex-specific modifiers can obviate the requirement for PRDM9 in mice. Specifically, the meiotic DNA damage checkpoint protein CHK2 acts as a modifier allowing female-specific fertility in the absence of PRDM9. We also report that, in the absence of PRDM9, a PRDM9-independent recombination system is compatible with female meiosis and fertility, suggesting sex-specific regulation of meiotic recombination, a finding with implications for speciation.

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Section: Discussionmentioning

confidence: 99%

Section: Sex-specific Requirement For Prdm9-dependent Histone Methyltmentioning

confidence: 95%

Sexual dimorphism in the meiotic requirement for PRDM9: A mammalian evolutionary safeguard

et al. 2020

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“…REC8 and RAD21L show mutually exclusive localization along the axis, forming distinct cohesin-enriched domains [16,17]. Genetic studies demonstrated that REC8 and RAD21L play different roles in sister chromatid cohesion, DSB formation, meiotic recombination, and homolog pairing/synapsis [20][21][22][23][24][25]. Thus, it is assumed that these meiosis-specific chromosome events are exerted through specific actions of REC8 and RAD21L to the axis binding factors during early meiotic prophase.…”

Section: Introductionmentioning

confidence: 99%

Meiotic cohesins mediate initial loading of HORMAD1 to the chromosomes and coordinate SC formation during meiotic prophase

et al. 2020

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During meiotic prophase, sister chromatids are organized into axial element (AE), which underlies the structural framework for the meiotic events such as meiotic recombination and homolog synapsis. HORMA domain-containing proteins (HORMADs) localize along AE and play critical roles in the regulation of those meiotic events. Organization of AE is attributed to two groups of proteins: meiotic cohesins REC8 and RAD21L; and AE components SYCP2 and SYCP3. It has been elusive how these chromosome structural proteins contribute to the chromatin loading of HORMADs prior to AE formation. Here we newly generated Sycp2 null mice and showed that initial chromatin loading of HORMAD1 was mediated by meiotic cohesins prior to AE formation. HORMAD1 interacted not only with the AE components SYCP2 and SYCP3 but also with meiotic cohesins. Notably, HORMAD1 interacted with meiotic cohesins even in Sycp2-KO, and localized along cohesin axial cores independently of the AE components SYCP2 and SYCP3. Hormad1/Rad21L-double knockout (dKO) showed more severe defects in the formation of synaptonemal complex (SC) compared to Hor-mad1-KO or Rad21L-KO. Intriguingly, Hormad1/Rec8-dKO but not Hormad1/Rad21L-dKO showed precocious separation of sister chromatid axis. These findings suggest that meiotic cohesins REC8 and RAD21L mediate chromatin loading and the mode of action of HOR-MAD1 for synapsis during early meiotic prophase.

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“…MSCI is triggered by XY asynapsis in spermatocytes and is marked by sequestration of the sex chromosomes in the ‘sex body’ (23). Spermatocytes undergoing PRDM9-deficient meiotic arrest in B6 mice do not form a normal sex body, as unsynapsed autosomes and unrepaired DSBs compromise recruitment of silencing factors to sex chromosomes (8, 26, 27). This could potentially lead to failure of MSCI, triggering meiotic arrest of PRDM9-deficient spermatocytes (8, 26).…”

Section: Discussionmentioning

confidence: 99%

Sexual dimorphism in the meiotic requirement for PRDM9: a mammalian evolutionary safeguard

Powers

Dumont

Emori

et al. 2020

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In many mammals, genomic sites for recombination are determined by histone methyltransferase PRMD9. Mice lacking PRDM9 are infertile, but instances of fertility or semi-fertility in the absence of PRDM9 have been reported in mice, canines and a human female. Such findings raise the question of how the loss of PRDM9 is circumvented to maintain reproductive fitness. We show that genetic background and sex-specific modifiers can obviate the requirement for PRDM9 in mice. Specifically, the meiotic DNA damage checkpoint protein CHK2 acts as a modifier allowing female-specific fertility in the absence of PRDM9. We also report that in the absence of PRDM9, a PRDM9-independent recombination system is compatible with female meiosis and fertility, suggesting sex-specific regulation of meiotic recombination, a finding with implications for speciation.One Sentence SummarySex-specific modulation of a meiotic DNA damage checkpoint limits the requirement for PRDM9 in mammalian fertility.

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Prdm9 and Meiotic Cohesin Proteins Cooperatively Promote DNA Double-Strand Break Formation in Mammalian Spermatocytes

Abstract: Highlights d PRDM9-cohesin interactions promote efficient DSB formation at recombination sites d Cohesins promote axis localization of pre-DSB recombinosome proteins d Cohesin proteins facilitate SPO11 function d Cohesin deficiency affects DSBs at both PRDM9-dependent and-independent sites

Cited by 40 publications

References 69 publications

Sexual dimorphism in the meiotic requirement for PRDM9: A mammalian evolutionary safeguard

Sexual dimorphism in the meiotic requirement for PRDM9: A mammalian evolutionary safeguard

Meiotic cohesins mediate initial loading of HORMAD1 to the chromosomes and coordinate SC formation during meiotic prophase

Sexual dimorphism in the meiotic requirement for PRDM9: a mammalian evolutionary safeguard

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