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Dna replication in mitosis vs meiosis9/12/2023 During this process, referred to as origin melting, the DNA helix is unwound by the minichromosome maintenance (MCM) complex ( Labib and Diffley, 2001) and replication is initiated by the primase activity of DNA polymerase alpha ( Bell and Dutta, 2002). At the G1/S transition, firing of the pre-RC by cyclin-dependent kinases (CDK) and the Cdc7/ASK kinase ( Wuarin and Nurse, 1996 Masai and Arai, 2002) triggers a conformational change in the origin licensing complex resulting in recruitment of Cdc45, DNA polymerase alpha, replication protein A and elongation factors. ORC functions as a landing platform for Cdc6 and Cdt1 which in turn load the minichromosome maintenance complex (Mcm2-7) onto chromatin ( Lei and Tye, 2001). The initial step in origin licensing is binding of the origin recognition complex (ORC) to chromatin ( DePamphilis, 2003). Assembly of pre-RCs renders origins competent or `licensed' for DNA replication during S phase ( Blow and Hodgson, 2002). Initiation of chromosomal replication depends on sequential assembly of pre-replicative complexes (pre-RCs) at replication origins during late mitosis and early G1 phase of the mitotic cell cycle ( Mendez and Stillman, 2000 Dimitrova et al., 2002). Our data demonstrate a striking sexual dimorphism in the mechanisms repressing origin licensing and preventing untimely DNA synthesis during meiosis I, implicating a pivotal role for Geminin in maintaining integrity of the male germline genome. In striking contrast, we show that proliferation control during male gametogenesis is not linked to Cdc6 or Mcm2, but appears to be coordinated by the negative regulator Geminin with Cdt1 becoming rate-limiting in late prophase. Our studies demonstrate that Cdc6, Cdt1 and Mcm2 play a central role in coordinating growth during the proliferation-differentiation switch in somatic self-renewing systems and that Cdc6 expression is rate-limiting for acquisition of replication competence in primary oocytes. Geminin is a repressor of origin licensing that blocks Mcm2-7 loading onto origins. Cdc6 and Cdt1 play an essential role in DNA replication initiation by loading the Mcm2-7 complex, which is required for unwinding the DNA helix, onto chromosomal origins. We have investigated regulation of the origin licensing factors Cdc6, Cdt1, Mcm2 and Geminin in human somatic and germ cells. Studies in yeast, Drosophila melanogaster and Xenopus laevis have characterised the molecular machinery that constitutes the licensing system, but it remains to be determined how this important evolutionary conserved pathway is regulated in Homo sapiens. The DNA replication (or origin) licensing system ensures precise duplication of the genome in each cell cycle and is a powerful regulator of cell proliferation in metazoa.
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