Publications

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A
Anderson, LK, Royer SM, Page SL, McKim KS, Lai A, Lilly MA, Hawley RS.  2005.  Juxtaposition of C(2)M and the transverse filament protein C(3)G within the central region of Drosophila synaptonemal complex. Proc Natl Acad Sci U S A. 102:4482-7.Website
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Bhagat, R, Manheim EA, Sherizen DE, McKim KS.  2004.  Studies on crossover specific mutants and the distribution of crossing over in Drosophila females. Cytogenetic and Genome Res.. 107:160-71.
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Cesario, JM, Jang JK, Redding B, Shah N, Rahman T, McKim KS.  2006.  Kinesin 6 family member Subito participates in mitotic spindle assembly and interacts with mitotic regulators. J Cell Sci. 119:4770-80.Website
Cesario, J, McKim KS.  2011.  RanGTP is required for meiotic spindle organization and the initiation of embryonic development in Drosophila. J Cell Sci. 124:3797-810. AbstractWebsite
RanGTP is important for chromosome-dependent spindle assembly in Xenopus extracts. Here we report on experiments to determine the role of the Ran pathway on microtubule dynamics in Drosophila oocytes and embryos. Females expressing a dominant-negative form of Ran have fertility defects, suggesting that RanGTP is required for normal fertility. This is not, however, because of a defect in acentrosomal meiotic spindle assembly. Therefore, RanGTP does not appear to be essential or sufficient for the formation of the acentrosomal spindle. Instead, the most important function of the Ran pathway in spindle assembly appears to be in the tapering of microtubules at the spindle poles, which might be through regulation of proteins such as TACC and the HURP homolog, Mars. One consequence of this spindle organization defect is an increase in the nondisjunction of achiasmate chromosomes. However, the meiotic defects are not severe enough to cause the decreased fertility. Reductions in fertility occur because RanGTP has a role in microtubule assembly that is not directly nucleated by the chromosomes. This includes microtubules nucleated from the sperm aster, which are required for pronuclear fusion. We propose that following nuclear envelope breakdown, RanGTP is released from the nucleus and creates a cytoplasm that is activated for assembling microtubules, which is important for processes such as pronuclear fusion. Around the chromosomes, however, RanGTP might be redundant with other factors such as the chromosome passenger complex.
Colombie, N, Cullen CF, Brittle AL, Jang JK, Earnshaw WC, Carmena M, McKim K, Ohkura H.  2008.  Dual roles of Incenp crucial to the assembly of the acentrosomal metaphase spindle in female meiosis. Development. 135:3239-46.Website
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Das, A, Shah SJ, Fan B, Paik D, DiSanto DJ, Hinman A M, Cesario JM, Battaglia RA, Demos N, McKim KS.  2016.  Spindle Assembly and Chromosome Segregation Requires Central Spindle Proteins in Drosophila Oocytes.. Genetics. 202(1):61-75. Abstract
Oocytes segregate chromosomes in the absence of centrosomes. In this situation, the chromosomes direct spindle assembly. It is still unclear in this system which factors are required for homologous chromosome bi-orientation and spindle assembly. The Drosophila kinesin-6 protein Subito, although nonessential for mitotic spindle assembly, is required to organize a bipolar meiotic spindle and chromosome bi-orientation in oocytes. Along with the chromosomal passenger complex (CPC), Subito is an important part of the metaphase I central spindle. In this study we have conducted genetic screens to identify genes that interact with subito or the CPC component Incenp. In addition, the meiotic mutant phenotype for some of the genes identified in these screens were characterized. We show, in part through the use of a heat-shock-inducible system, that the Centralspindlin component RacGAP50C and downstream regulators of cytokinesis Rho1, Sticky, and RhoGEF2 are required for homologous chromosome bi-orientation in metaphase I oocytes. This suggests a novel function for proteins normally involved in mitotic cell division in the regulation of microtubule-chromosome interactions. We also show that the kinetochore protein, Polo kinase, is required for maintaining chromosome alignment and spindle organization in metaphase I oocytes. In combination our results support a model where the meiotic central spindle and associated proteins are essential for acentrosomal chromosome segregation.
Dorsett, D, Eissenberg JC, Misulovin Z, Martens A, Redding B, McKim K.  2005.  Effects of sister chromatid cohesion proteins on cut gene expression during wing development in Drosophila. Development. 132:4743-53.Website
Doubilet, S, McKim KS.  2007.  Spindle assembly in the oocytes of mouse and Drosophila--similar solutions to a problem. Chromosome Res. 15:681-96.Website
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Giunta, KL, Jang JK, Manheim EM, Subramanian G, McKim KS.  2002.  subito encodes a kinesin-like protein required for meiotic spindle pole formation in Drosophila melanogaster. Genetics. 160:1489-1501.
Gyuricza, MR, Manheimer KB, Apte V, Krishnan B, Joyce EF, McKee BD, McKim KS.  2016.  Dynamic and Stable Cohesins Regulate Synaptonemal Complex Assembly and Chromosome Segregation.. Current biology : CB. 26(13):1688-1698. Abstract
Assembly of the synaptonemal complex (SC) in Drosophila depends on two independent pathways defined by the chromosome axis proteins C(2)M and ORD. Because C(2)M encodes a Kleisin-like protein and ORD is required for sister-chromatid cohesion, we tested the hypothesis that these two SC assembly pathways depend on two cohesin complexes. Through single- and double-mutant analysis to study the mitotic cohesion proteins Stromalin (SA) and Nipped-B (SCC2) in meiosis, we provide evidence that there are at least two meiosis-specific cohesin complexes. One complex depends on C(2)M, SA, and Nipped-B. Despite the presence of mitotic cohesins SA and Nipped-B, this pathway has only a minor role in meiotic sister-centromere cohesion and is primarily required for homolog interactions. C(2)M is continuously incorporated into pachytene chromosomes even though SC assembly is complete. In contrast, the second complex, which depends on meiosis-specific proteins SOLO, SUNN, and ORD is required for sister-chromatid cohesion, localizes to the centromeres and is not incorporated during prophase. Our results show that the two cohesin complexes have unique functions and are regulated differently. Multiple cohesin complexes may provide the diversity of activities required by the meiotic cell. For example, a dynamic complex may allow the chromosomes to regulate meiotic recombination, and a stable complex may be required for sister-chromatid cohesion.
Głuszek, AA, Cullen FC, Li W, Battaglia RA, Radford SJ, Costa MF, McKim KS, Goshima G, Ohkura H.  2015.  The microtubule catastrophe promoter Sentin delays stable kinetochore-microtubule attachment in oocytes.. The Journal of cell biology. 211(6):1113-20. Abstract
The critical step in meiosis is to attach homologous chromosomes to the opposite poles. In mouse oocytes, stable microtubule end-on attachments to kinetochores are not established until hours after spindle assembly, and phosphorylation of kinetochore proteins by Aurora B/C is responsible for the delay. Here we demonstrated that microtubule ends are actively prevented from stable attachment to kinetochores until well after spindle formation in Drosophila melanogaster oocytes. We identified the microtubule catastrophe-promoting complex Sentin-EB1 as a major factor responsible for this delay. Without this activity, microtubule ends precociously form robust attachments to kinetochores in oocytes, leading to a high proportion of homologous kinetochores stably attached to the same pole. Therefore, regulation of microtubule ends provides an alternative novel mechanism to delay stable kinetochore-microtubule attachment in oocytes.
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Hari, KL, Santerre A, Sekelsky JJ, McKim KS, Boyd JB, Hawley RS.  1995.  The mei-41 gene of D. melanogaster is a structural and function homolog of the human ataxia telangiectasia gene. Cell. 82:815-821.
Hawley, RS, McKim KS, Arbel T.  1993.  Meiotic segregation in Drosophila melanogasterfemales: molecules, mechanisms and myths. Ann. Rev. Genet.. 27:281-317.
Hawley, RS, Irick HA, Zitron AE, Haddox DA, Lohe AR, New C, Whitley MD, Arbel T, Jang JK, McKim KS et al..  1993.  There are two mechanisms of achiasmate segregation in Drosophila females, one of which requires heterochromatic homology. Developmental Genetics. 13:440-467.
Horner, V.L., Czank, Z., Jang, J.K., Singh, N., Williams, B.C., Puro, J., Kubli, E., Hanes, S.D., McKim, K.S., Wolfner, M.F. et al..  2006.  The Drosophila calcipressin sarah is Required for several aspects of egg activation. Curr Biol. 16:144-6.Website
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Jang, JK, Sherizen DE, Bhagat R, Manheim EA, McKim KS.  2003.  Relationship of DNA double-strand breaks to synapsis in Drosophila. J. Cell. Sci.. 116:3069-3077.
Joyce, EF, Pedersen M, Tiong S, White-Brown SK, Paul A, Campbell SD, McKim KS.  2011.  Drosophila ATM and ATR have distinct activities in the regulation of meiotic DNA damage and repair. J Cell Biol. 195:359-67. AbstractWebsite
Ataxia telangiectasia-mutated (ATM) and ataxia telangiectasia-related (ATR) kinases are conserved regulators of cellular responses to double strand breaks (DSBs). During meiosis, however, the functions of these kinases in DSB repair and the deoxyribonucleic acid (DNA) damage checkpoint are unclear. In this paper, we show that ATM and ATR have unique roles in the repair of meiotic DSBs in Drosophila melanogaster. ATR mutant analysis indicated that it is required for checkpoint activity, whereas ATM may not be. Both kinases phosphorylate H2AV (gamma-H2AV), and, using this as a reporter for ATM/ATR activity, we found that the DSB repair response is surprisingly dynamic at the site of DNA damage. gamma-H2AV is continuously exchanged, requiring new phosphorylation at the break site until repair is completed. However, most surprising is that the number of gamma-H2AV foci is dramatically increased in the absence of ATM, but not ATR, suggesting that the number of DSBs is increased. Thus, we conclude that ATM is primarily required for the meiotic DSB repair response, which includes functions in DNA damage repair and negative feedback control over the level of programmed DSBs during meiosis.
Joyce, EF, Paul A, Chen KE, McKim KS.  2012.  Multiple Barriers to Non-homologous DNA End Joining During Meiosis in Drosophila. Genetics. 191:739-46. AbstractWebsite
Repair of meiotic double-strand breaks (DSBs) uses the homolog and recombination to yield crossovers while alternative pathways such as nonhomologous end-joining (NHEJ) are suppressed. Our results indicate that NHEJ is blocked at two steps of DSB repair during meiotic prophase: first by the activity of the MCM-like protein MEI-218 that is required for crossover formation and, second, by Rad51-related proteins SPN-B (XRCC3) and SPN-D (RAD51C) that physically interact and promote homologous recombination. We further show that the MCM-like proteins also promote the activity of the DSB repair checkpoint pathway, indicating an early requirement for these proteins in DSB processing. We propose that when a meiotic DSB is formed in the absence of both MEI-218 and SPN-B or SPN-D, a DSB substrate is generated that can enter the NHEJ repair pathway. Indeed, due to its high error rate, multiple barriers may have evolved to prevent NHEJ activity during meiosis.