https://mcb.berkeley.edu/courses/mcb230/WEB/PAPERS/jenuwein%20cell%20suv39%20genome%20stability%20copy.pdf

Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability.

Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway.

▪ Abstract Meiotic chromosomes have been studied for many years, in part because of the fundamental life processes they represent, but also because meiosis involves the formation of homolog pairs, ...

Meiotic chromosomes: integrating structure and function.

Mammalian genomes employ heritable cytosine methylation in the long-term silencing of retrotransposons and genes subject to genomic imprinting and X chromosome inactivation. Little is known of the mechanisms that direct cytosine methylation to specific sequences. Here we show that DNA methyltransferase 3-like (Dnmt3L (ref. 1)) is expressed in testes during a brief perinatal period in the non-dividing precursors of spermatogonial stem cells at a stage where retrotransposons undergo de novo methylation. Deletion of the Dnmt3L gene prevented the de novo methylation of both long-terminal-repeat (LTR) and non-LTR retrotransposons, which were transcribed at high levels in spermatogonia and spermatocytes. Loss of Dnmt3L from early germ cells also caused meiotic failure in spermatocytes, which do not express Dnmt3L. Whereas dispersed repeated sequences were demethylated in mutant germ cells, tandem repeats in pericentric regions were methylated normally. This result indicates that the Dnmt3L protein might have a function in the de novo methylation of dispersed repeated sequences in a premeiotic genome scanning process that occurs in male germ cells at about the time of birth.

Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L.

Oct4-induced pluripotency in adult neural stem cells

A.H.F.M. Peters (corresponding author), A.W. Plug, M.J. van Vugt and P. de Boer are at the Department of Genetics, Wageningen Institute of Animal Sciences, Wageningen Agricultural University, Dreijenlaan 2, NL-6703 HA Wageningen, The Netherlands. Tel: ( 31) 317 483147; Fax: ( 31) 317 483929; Email: Antoine.Peters@alg.vf.wau.nl. A.W. Plug is now at the Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.

A drying-down technique for the spreading of mammalian meiocytes from the male and female germline.

Homologous chromosome synapsis and meiotic recombination are facilitated by several meiosis-specific structures: the synaptonemal complex (SC), and two types of meiotic nodules: (1) early meiotic nodules (MNs), also called zygotene nodules or early recombination nodules, and (2) late recombination nodules (RNs). The former are thought to be nucleoprotein complexes involved in the check for homology preceding, or accompanying synapsis, while the latter have been shown to be involved in reciprocal recombination. We have examined by immunocytochemistry the meiotic localization of a series of proteins at sites along the asynapsed axial elements prior to homologous synapsis and at sites along the SCs following synapsis. Several of the proteins examined have been implicated in repair/recombination and include RAD51, a mammalian homolog of the Escherichia coli RecA protein; Replication Protein-A (RPA), a single-strand DNA binding protein; and MLH1, a mismatch repair protein which is a homolog of the E. coli MutL protein. In addition two proteins were examined that have been implicated in meiotic checkpoints: ATM, the protein mutated in the human disease Ataxia Telangiectasia, and ATR, another member of the same family of PIK kinases. We present evidence that these proteins are all components of meiotic nodules and document changes in protein composition of these structures during zygonema and pachynema of meiotic prophase in mouse spermatocytes. These studies support the supposition that a subset of MNs are converted into RNs. However, our data also demonstrate changes in protein composition within the context of early MNs, suggesting a differentiation of these nodules during the process of synapsis. The same changes in protein composition occurred on both the normal X axis, which has no homologous pairing partner in spermatocytes, and on the axes of aberrant chromosomes that nonhomologously synapse during synaptic adjustment. These findings suggest that DNA sequences associated with MNs still must undergo an obligatory processing, even in the absence of interactions between homologous chromosomes.

Changes in protein composition of meiotic nodules during mammalian meiosis

ATM is a member of the phosphatidylinositol 3-kinase (PIK)like kinases, some of which are active in regulating DNA damage-induced mitotic cell-cycle checkpoints1,2 ATM also plays a role in meiosis Spermatogenesis in Atm−/− male mice is disrupted, with chromosome fragmentation leading to meiotic arrest3; in human patients with ataxia-telangiectasia (A-T), gonadal atrophy is common Immuno-localization studies indicate that ATM is associated with sites along the synaptonemal complex (SC), the specialized structure along which meiotic recombination occurs4 Recombination, preceded by pairing of homologous chromosomes, is thought to require heteroduplex formation between homologous DNA, followed by strand exchange These early meiotic steps (entailing the formation and processing of meiotic recombination intermediates with DNA-strand interruptions) require ssDNA-binding proteins such as replication protein A (RPA; refs 5-7) In somatic cells, DNA damage induces ATM-dependent phosphorylation of RPA8,9 We demonstrate here that ATM and RPA co-localize along synapsed meiotic chromosomes and at sites where interactions between ectopic homologous chromosome regions appear to initiate In Atm−/− meiotic prophase sper-matocytes, immuno-localization shows that RPA is present along synapsing chromosomes and at sites of fragmentation of the SC These results suggest that RPA and ATM co-localize at sites where interhomologous-DNA interactions occur during meiotic prophase and where breaks associated with meiotic recombination take place after synapsis, implying a possible functional interaction between these two proteins

ATM and RPA in meiotic chromosome synapsis and recombination

Mice that are double heterozygous for the semi-identical T(1;13)70H and T(1;13)1Wa reciprocal translocations display a great variation in male fertility. The synaptic behaviour of the different translocation chromosomes of adult males was studied in relation to this parameter. Juvenile males and embryonic females (16 and 18 days old) were included for comparison. In agreement with the minor differences in the translocation breakpoint positions, two differently sized heteromorphic bivalents are formed in meiotic prophase of both sexes (a quadrivalent was never encountered). Synaptonemal complex (SC) configurations of both bivalents in either sex are characterized by a high degree of non-homologous synapsis at zygotene-early pachytene. The rate of synaptic adjustment during pachytene is dependent on the size of the heteromorphic bivalent and varies between the sexes. Differences in SC configuration and morphology of the small heteromorphic bivalent in particular exist between the sexes and between animals. In males, this correlates with different degrees of fertility. Normal SC morphology in a fully synapsed small heteromorphic bivalent is an important determinant of successful meiosis and spermatogenesis. Moreover, aberrant synapsis favours the ‘unsaturated pairing site’ model as the primary cause for male sterility.

P. de Boer

Papers

A drying-down technique for the spreading of mammalian meiocytes from the male and female germline.

Changes in protein composition of meiotic nodules during mammalian meiosis

ATM and RPA in meiotic chromosome synapsis and recombination

Meiosis in carriers of heteromorphic bivalents: sex differences and implications for male fertility.