{"id":480,"date":"2023-07-18T12:23:13","date_gmt":"2023-07-18T19:23:13","guid":{"rendered":"https:\/\/live-usc-dornsife.pantheonsite.io\/pombenet\/?page_id=480"},"modified":"2024-07-03T09:12:03","modified_gmt":"2024-07-03T16:12:03","slug":"forsburg-lab-research-meiosis","status":"publish","type":"page","link":"https:\/\/dornsife.usc.edu\/pombenet\/forsburg-lab-research-meiosis\/","title":{"rendered":"Forsburg Lab Research: Meiosis"},"content":{"rendered":"\n\n  \n    \n\n\n\n\n\n\n<div\n  class=\"cc--component-container cc--rich-text \"\n\n  \n  \n  \n  \n  \n  \n  >\n  <div class=\"c--component c--rich-text\"\n    \n      >\n\n    \n      \n<div class=\"f--field f--wysiwyg\">\n\n    \n  <p>We started looking at meiosis a number of years ago, and we have several ongoing projects related to the role of replication proteins and genome stability in meiotic progression, particularly meiotic S phase.<\/p>\n<p>&nbsp;<\/p>\n<div style=\"align-items: center; display: flex;\">\n<div class=\"video-embed\"><iframe loading=\"lazy\" id=\"video-player-5bda762594a23\" src=\"https:\/\/www.youtube.com\/channel\/UCrrTi-I1DDmDfdytjfjraKg\" name=\"video-player-5bda762594a23\" width=\"700\" height=\"500\" allowfullscreen=\"allowfullscreen\" title=\"video player\"><\/iframe><\/div>\n<\/div>\n<p>&nbsp;<\/p>\n<p>The nucleus is labeled with GFP-histone, and you can see the characteristic &#8220;horsetailing&#8221; as the nuclei go back and forth during meiotic prophase, which serves to shake the chromosomes into proper position for recombination. then you can see the coordination of the meiosis I (MI) and meiosis II (MII) divisions.<\/p>\n<div class=\"article cf\">\n<div class=\"html-content\">\n<p>Check out this fission yeast page for\u00a0<a title=\"Meiosis\" href=\"\/pombenet\/meiosis\/\" rel=\"self\">background information about meiosis<\/a>, why it&#8217;s interesting, and why we use fission yeast to study this fundamental process, which has broad implications for human health and development.<\/p>\n<p>&nbsp;<\/p>\n<\/div>\n<\/div>\n<div class=\"article cf\">\n<h3 class=\"article-title\">Some MCM Mutants do not Affect Meiosis<\/h3>\n<div class=\"html-content\">\n<p>Our first studies presented us with a surprising result:\u00a0<em>mcm<\/em>\u00a0mutants that block the cell cycle nevertheless completed meiosis. That is, under conditions where there is a lethal block to cell cycle progression, the cells merrily complete meiosis.<\/p>\n<p>What&#8217;s that about?<\/p>\n<p>The parsimonious explanation, which we suggested at the time, is that MCMs aren&#8217;t required for DNA replication in meiosis, because certainly these lethal alleles had no effect. As described on our\u00a0<a title=\"Our research: Genome stability\" href=\"\/pombenet\/genome-stability\/\" rel=\"self\">Genome Stability page,\u00a0<\/a>the same mutations in cycling cells cause catastrophic DNA damage and activation of the DNA damage checkpoint. However, using different protocols, Paul Nurse&#8217;s and Stephen Kearsey&#8217;s labs were able to show that some\u00a0<em>mcm<\/em>\u00a0mutations do block meiosis.<\/p>\n<p>The answer is in the conundrum that\u00a0<em>mcm-ts<\/em>\u00a0alleles we used are separation of function mutations, which I described on the\u00a0<a title=\"Our research: Meiosis\" href=\"\/pombenet\/forsburg-lab-research-meiosis\/\" rel=\"self\">MCM page.<\/a>\u00a0They are permissive for initiation, but defective for completion of vegetative DNA replication, causing massive damage. In contrast, Kearsey and Nurse used initiation mutants. And initiation mutants blocked meiosis. All three labs were correct. But how could a mutant that causes catastrophic DNA damage and activation of the DNA damage checkpoint in vegetative cells have no effect on meiosis?<\/p>\n<p>There are two parts to the answer. First of all, the arrest of the\u00a0<em>mcm<\/em>\u00a0mutants in S phase depends on activation of the DNA damage checkpoint, which is triggered by the catastrophic damage they cause. Dan Pankratz discovered that the\u00a0<strong>DNA damage checkpoint is not activated in meiosis.\u00a0<\/strong>This makes some sense, since one of the essential activities of meiosis is to induce programmed double stranded breaks to act as recombination substrates. So, no checkpoint, means our\u00a0<em>mcm<\/em>\u00a0mutants don&#8217;t arrest. (Why the checkpoint is not active, is a subject we are investigating). This explains Mike Catlett &#8216;s observation that in mutants lacking both homologues of the Rad54 homologous recombination protein (Rhp54, the mitotic gene, and Rdh54\/Tid1, the meiotic gene) , which are completely defective in DSB repair, meiosis still proceeds.<\/p>\n<p>But if we eliminate the checkpoint from\u00a0<em>mcm<\/em>\u00a0mutants in vegetative cells, the cells undergo cell death as they attempt to transition mitosis. Why are the meiotic cells able to tolerate this? We propose that it&#8217;s because meiotic cells are\u00a0<em>designed<\/em>\u00a0to deal with breaks, of the sort our\u00a0<em>mcm<\/em>\u00a0mutants cause. There&#8217;s a whole meiosis-specific apparatus for this. We&#8217;re currently working to verify this hypothesis.<\/p>\n<p>&nbsp;<\/p>\n<\/div>\n<\/div>\n<div class=\"article cf\">\n<h3 class=\"article-title\">DDK, Alkylation damage, and Meiosis<\/h3>\n<div class=\"html-content\">\n<p>As described on our\u00a0<a title=\"Our research: DDK\" href=\"\/pombenet\/ddk\/\" rel=\"self\">DDK<\/a>\u00a0page, we have used truncation alleles of the Dfp1 subunit of DDK kinase to separate its different functions. A short C-terminal truncation of Dfp1, orginally called\u00a0<em>rad35\u00a0<\/em>and which we call\u00a0<em>dfp1-r35,\u00a0<\/em>eliminates a conserved zinc-finger region of the protein, and confers sensitivity to alkylating damage and defects in induced mutagenesis. However, this allele also has defects in meiosis. Work from Hisao Masai and others suggests that DDK is required for the recruitment of the endonuclease Rec12\/Spo11 to induce programmed double strand breaks in meiosis. However,\u00a0<em>dfp1-r35<\/em>\u00a0shows multiple meiotic defects, including disruption of meiotic transcription and cohesin phosphorylation.<\/p>\n<p>A broader question is whether there is anything in common between meiosis and alkylation damage response, that would explain why the same mutation affects both. That&#8217;s a question addressed by Tara Mastro.<\/p>\n<p>&nbsp;<\/p>\n<\/div>\n<\/div>\n<div class=\"article cf\">\n<h3 class=\"article-title\">Review on Meiosis<\/h3>\n<div class=\"html-content\">\n<p><strong>Forsburg<\/strong>, S. L. (2002). Only connect: linking meiotic S phase to downstream events.\u00a0<a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/11983163\" rel=\"self\">Mol. Cell. 9:703-11<\/a><\/p>\n<div><\/div>\n<\/div>\n<\/div>\n<div class=\"article cf\">\n<h3 class=\"article-title\">Our Primary Research Papers on Meiosis<\/h3>\n<div class=\"html-content\">\n<ul class=\"(null)\">\n<li>Mastro TL, Forsburg SL. (2014) Increased Meiotic Crossovers and Reduced Genome Stability in Absence of Schizosaccharomyces pombe Rad16 (XPF)<a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/25293972\" rel=\"self\">. Genetics.<\/a>\u00a0Oct 6. pii: genetics.114.171355. [Epub ahead of print]<\/li>\n<li>Le, AH, Mastro, T.L,\u00a0<strong>Forsburg SL.<\/strong>\u00a0(2013) The C-terminus of S. pombe DDK subunit Dfp1 is required for meiosis-specific transcription and cohesin cleavage.\u00a0<a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/23862021\" rel=\"self\">Biol Open. 2013 Jun 11;2(7):728-38.<\/a><\/li>\n<li>Pankratz, D.G., and\u00a0<strong>Forsburg<\/strong>, S.L. (2005) Meiotic S-phase damage activates recombination without check\u00acpoint arrest .\u00a0<a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/15689488\" rel=\"self\">Mol. Biol. Cell16:1651-1660.<\/a>\u00a0PMC1073649<\/li>\n<li>Catlett, M.G. and\u00a0<strong>Forsburg<\/strong>, S.L. (2003). S. pombe Rdh54 (TID1) acts with Rhp54 (RAD54) to repair meiotic double strand breaks<a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/14551247\" rel=\"self\">. Mol. Biol. Cell 14:4707-4720\u00a0<\/a>w\/ video online.. PMC266785<\/li>\n<li><strong>Forsburg<\/strong>, S.L. and Hodson, J.A. (2000) Mitotic replication initiation proteins are not required for S. pombe pre-meiotic S phase.<a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/10888871\" rel=\"self\">Nat. Genet. 25:263-268<\/a><\/li>\n<li>Bishop, D.T., Macdonald, H., Gould, K.L., and\u00a0<strong>Forsburg<\/strong>, S.L. (2000) Isolation of an essential S. pombe gene, prp31+, linking splicing and meiosis.\u00a0<a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/10871341\" rel=\"self\">Nucl Acids Res. 28: 2214-2220.\u00a0<\/a>PMC102626<\/li>\n<li><strong>Forsburg<\/strong>, S.L. and Nurse, P. (1994). Analysis of the S. pombe cyclin puc1: evidence for a role in cell cycle exit.\u00a0<a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/8006074\" rel=\"self\">J. Cell Sci. 107: 601-613<\/a><\/li>\n<\/ul>\n<p><strong><a title=\"Publications\" href=\"\/pombenet\/forsburg-publications\/\" rel=\"self\">See the complete Forsburg Lab Publication list<\/a><\/strong><\/p>\n<\/div>\n<\/div>\n\n\n\n<\/div>\n\n\n  <\/div><\/div>\n","protected":false},"excerpt":{"rendered":"","protected":false},"author":354,"featured_media":0,"parent":0,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"page-content-detail.php","meta":{"_acf_changed":false,"footnotes":""},"class_list":["post-480","page","type-page","status-publish","hentry"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.1.1 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Forsburg Lab Research: Meiosis - PombeNet Forsburg Lab<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/dornsife.usc.edu\/pombenet\/forsburg-lab-research-meiosis\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Forsburg Lab Research: Meiosis - 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