Dynamic localization of SMC5/6 complex proteins during mammalian meiosis and mitosis implies functions in distinct chromosome processes

Abstract

SummaryFour members of the structural maintenance of chromosome (SMC) protein family have essential functions in chromosome condensation (SMC2/4) and sister-chromatid cohesion (SMC1/3). The SMC5/6 complex has been implicated in chromosome replication, DNA repair and chromosome segregation in somatic cells, but its possible functions during mammalian meiosis are unknown. Here, we show in mouse spermatocytes that SMC5 and SMC6 are located at the central region of the synaptonemal complex from zygotene until diplotene. During late diplotene both proteins load to the chromocenters, where they colocalize with DNA Topoisomerase IIa, and then accumulate at the inner domain of the centromeres during the first and second meiotic divisions. Interestingly, SMC6 and DNA Topoisomerase IIa colocalize at stretched strands that join kinetochores during the metaphase II to anaphase II transition, and both are observed on stretched lagging chromosomes at anaphase II following treatment with Etoposide. During mitosis, SMC6 and DNA Topoisomerase IIa colocalize at the centromeres and chromatid axes. Our results are consistent with the participation of SMC5 and SMC6 in homologous chromosome synapsis during prophase I, chromosome and centromere structure during meiosis I and mitosis and, with DNA Topoisomerase IIa, in regulating centromere cohesion during meiosis II.

Conditional mutation of Smc5 in mouse embryonic stem cells perturbs condensin localization and mitotic progression

“…This is consistent with what was previously published using MEFs (Gomez et al, 2013). These observations are in contrast to what has been reported using RPE-1 cells, where Smc5 and Smc6 are enriched within the nucleus during interphase, but then greatly diminished from the chromatin during mitosis (Gallego-Paez et al, 2014).…”

“…Smc5 mutation in mESCs leads to abnormal distribution of condensin along chromosomes Based on previous siRNA-mediated knockdown studies of the Smc5/6 complex in mammalian cell lines, we hypothesized that the chromosome bridges and lagging chromosomes we observed after Smc5 depletion could be attributed to defects in chromosome cohesion, condensation and/or topoisomerase IIα (Topo IIα) function Gallego-Paez et al, 2014;Gomez et al, 2013).…”

“…The distinct roles of the Smc5/6 complex in mammalian cells have yet to be defined. However, localization and small interfering RNA (siRNA) knockdown studies in mammalian cells suggest that the complex is required during DNA replication, DNA repair and chromosome segregation Gallego-Paez et al, 2014;Gomez et al, 2013).…”

Meiotic Recombination: The Essence of Heredity

“…In Arabidopsis, analysis of an mms21 mutant reveals phenotypes consistent with defective joint molecule processing including anaphase bridges, chromosome missegregation, and fragmentation (Liu et al 2014a). In mammals, SMC5/6 localizes to synaptonemal complex, consistent with a role in meiotic recombination (Gomez et al 2013;Verver et al 2014), but mutant analysis is currently lacking.…”

Recombination, Pairing, and Synapsis of Homologs during Meiosis

“…For example, dimers of the large coiled-coil protein Zip1/SCP1/ SYCP1/C(3)G/SYP-1/ZEP1/ZIP1 form the transverse filaments of the SC central region in all organisms (e.g., Higgins et al 2005;Hawley 2011;Miao et al 2013). They were previously thought to be the sole SC central element components, but they are in fact associated with additional proteins different in number, localization, and perhaps function from one organism to the other: SYCE1, SYCE2, SYCE3, and Tex12 in mammals; Cona in Drosophila, SYP-2, SYP-3, SYP-4 in worm; and Ecm11, Gmc2 in budding yeast (reviewed in Bolcun-Filas et al 2007;Hawley 2011;Schild-Prüfert et al 2011;Davies et al 2012;Fraune et al 2012;Gó mez et al 2013;Humphryes et al 2013). However, despite the identification of several new AE and central region components in recent years, we are only beginning to understand how they interact precisely to form the SC (Davies et al 2012), how they are regulated, and, more importantly, what is/are the function(s) of the SC.…”