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Elucidation of Factors Impacting Homologous Recombination ELUCIDATION OF FACTORS IMPACTING HOMOLOGOUS RECOMBINATION IN MAMMALIAN MEIOSIS by SHEILA M. CHERRY Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Thesis Advisor: Dr. Terry J. Hassold Department of Genetics CASE WESTERN RESERVE UNIVERSITY January, 2007 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of ______________________________________________________ candidate for the Ph.D. degree *. (signed)_______________________________________________ (chair of the committee) ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. 1 Table of Contents Table of Contents……...……………………………………………..…………………..1 List of Tables…………...……………………………………………………..………….2 List of Figures………..………………………………………………………………..…3 Abstract…………………………………………………………………………………...5 Chapter One: Introduction…………………………………………………………….7 Chapter Two: Environment and Recombination………………..….………………..40 Chapter Three: Early recombination events and crossover control…..………..……..77 Chapter Four: Understanding late recombination events……..…….………………112 Chapter Five: Summary and Future Directions…………………………………….135 Bibliography…………………………………………………………………………...148 2 List of Tables Table 2-1: Mean numbers of autosomal MLH1 foci for control and CP-treated age-matched controls………………..………….…………70 Table 2-2: Sperm chromosome complements in control and CP-treated males.….71 Table 3-1: Average number of RAD51 foci in pachytene stage meiocytes from Mre11ATLD1/ATLD1 mutant and control mice………………………96 Table 3-2: Average number of MLH1 foci in pachytene stage meiocytes from Mre11ATLD1/ATLD1 and Nbs1ΔB/ΔB mutant and control mice……………102 3 List of Figures Figure 1-1: Differential timing of gametogenesis in mammals……………………….10 Figure 1-2: Meiosis…..………………………………………………………………..13 Figure 1-3: Substages of Meiotic Prophase…………………………………………...15 Figure 1-4: The temporal progression of the synaptonemal complex………………...17 Figure 1-5: The Double Holliday Junction model of recombination………………….21 Figure 1-6: Proposed model of MutS/MutL homolog interactions in mammalian meiosis…………………………………………………………………...25 Figure 2-1: Cisplatin exposure paradigm, showing the length of time between CP injection and analysis of spermatocytes or mature sperm…………...46 Figure 2-2: Mean (± S.E.) testis weight (g) and length (mm) for CP-treated and sham-injected control littermates………………………………………..53 Figure 2-3: Prophase germ cell distributions for CP-treated vs. control males……....55 Figure 2-4: Hematoxylin and eosin-stained testis cross-sections for control and CP-treated males.......................................................................................58 Figure 2-5: Mean (± S.E.) proportions of tubules exhibiting 4 or more TUNEL-positive germ cells (TUNEL-positive, black bars) or 3 or fewer TUNEL-positive germ cells (TUNEL-negative, gray bars) from testis cross-sections of control and CP-treated males……………………………………………61 Figure 2-6: TUNEL preparations for control and CP-treated males…………………63 Figure 2-7: Mean (± S.E.) sperm counts for CP-treated and control littermates…….66 Figure 2-8: Synaptonemal complex aberrations in CP-treated males………………...68 Figure 3-1: Altered distribution of prophase meiocytes from Mre11ATLD1/ATLD1 and Nbs1∆B/∆B mice…………………………………………………………...89 Figure 3-2: Synaptonemal complex (SC) assembly defects in prophase meiocytes from Mre11ATLD1/ATLD1 and Nbs1∆B/∆B mice………………………………93 4 Figure 3-3: Persistent RAD51 foci and altered RAD51 distribution in pachytene stage meiocytes from Mre11ATLD1/ATLD1 mice…………………………..98 Figure 3-4: Crossover distribution and location is altered in Mre11ATLD1/ATLD1 and Nbs1∆B/∆B spermatocytes………………………………………….104 Figure 4-1: Proportion of meiocytes at various substages of prophase…………….120 Figure 4-2: Synaptic abnormalities in Pms2-/- meiocytes…………………………..123 Figure 4-3: MLH1 localization in pachytene cells………………………………….125 Figure 4-4: Chromosomal location of chiasmata in diakinesis oocytes……………..129 Figure 5-1: Schematic of the approach to studying recombination via germ cell transplantation…………………………………………………………145 5 Elucidation of Factors Impacting Homologous Recombination in Mammalian Meiosis Abstract by SHEILA M. CHERRY Meiotic recombination, or crossing-over, maintains associations between homologous chromosomes as they prepare to enter the cellular divisions. If this process is perturbed, meiotic abnormalities ensue. Indeed, in humans an abnormal number or location of recombination events is the only known molecular correlate of aneuploidy (monosomy or trisomy). As such abnormalities are the leading known cause of miscarriages and mental retardation in our species, understanding the link between recombination and chromosome segregation is of great clinical significance. Accordingly, in my thesis research I have utilized both environmental and genetic approaches to understand the way in which crossovers (COs) are positioned in the mammalian genome, and how CO placement affects chromosome segregation. I conducted two sets of studies, analyzing mouse meiosis in each instance. First, the meiotic environment was altered via exposure to a chemotoxin which would introduce additional DNA breaks in early meiotic cells. The results of this study suggest the presence of crossover homeostasis in mammals, a mechanism to maintain the number of crossovers when the number of DSBs is modified. Second, to understand crossover control, the recombination pathway was altered via genetic mutation. Disruptions in the early or late DSB repair processes (Mre11 and Pms2 mutants, respectively) indicated that 6 the fidelity of recombination depends partly on the successful completion of synapsis, and that, as in humans, crossover placement is important for proper chromosome segregation. 7 Chapter One: Introduction Homologous recombination (HR), long associated with the generation of genetic diversity among organisms, has a second, more immediate, role: ensuring the equal segregation of chromosomes during the meiotic divisions. Recombination is essential to meiosis, and the general features of the process are well-understood from studies in a variety of organisms. The “central dogma” dictates that double-strand breaks (DSBs; the first step in recombination) occur during prophase; homologous chromosomes pair and align; synapsis and crossovers occur between homologs, with the timing of these events varying considerably among different species; and lastly, crossovers fully resolve and homologs desynapse, allowing the cell to continue through meiosis (see Hassold et al., 2000 for review). The link between recombination and proper chromosome segregation is crucial, though not completely understood. What is clear, however, is that recombination has clinical ramifications for humans; even minor changes in the frequency and/or placement of recombination events may result in a failure of homologs to segregate to opposite poles, thereby leading to an increase in germ cell aneuploidy (Warren et al., 1987; Ferguson et al., 1996; Lamb et al., 1997; Koehler and Hassold, 1998). Aneuploidy is the most common cause both of spontaneous abortions in humans and of mental retardation in liveborns (reviewed by Hassold et al., 1996). Exploring the cause-and-effect relationship between recombination and aneuploidy remains important. 8 Meiosis To understand homologous recombination, one must appreciate the context in which recombination occurs. Meiosis is the specialized cell cycle whereby haploid gametes are produced from diploid progenitor cells. The meiotic cycle varies both in timing and duration- not only among organisms, but even between sexes (Figure 1-1). In most male mammals, meiosis coincides with sexual maturity and new germ cells constantly enter the spermatogenic pathway, such that meiosis is underway throughout adult life. In most mammalian females, however, germ cells enter meiosis nearly synchronously during fetal development. Around birth, oocytes are arrested at the end of prophase. The first meiotic division completes at ovulation, oocytes arrest again at metaphase II and the second division is completed at the time of fertilization (see Hunt and Hassold, 2002). In line with these temporal differences, individual stages of the meiotic cycle are often of different duration between the sexes. For example, in the male mouse prophase lasts nearly two weeks, while in the female the same stage lasts for only several days. Similarly, the time from meiotic entry to the development of a mature germ cell may be several months in the mammalian male and several decades in the mammalian female! These fundamental differences will become quite important later when we consider disparate phenotypes of male and female meiotic mutants. We know that haploid germ cells are the end product, but what specifically happens during meiosis? During pre-meiotic S phase, the DNA replicates; significantly, this one round of DNA replication will be followed by two successive cell divisions without an intervening S phase (Figure 1-2). Following DNA replication, meiotic 9 Figure 1-1: Differential timing of gametogenesis in mammals. Female development is depicted across the top, male development across the bottom, with age increasing
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