José Ángel Suja Sánchez (firstname.lastname@example.org) – PI
Alberto Viera Vicario (email@example.com), Staff scientist
Rocío Gómez Lencero (firstname.lastname@example.org), Staff scientist
Inés Berenguer López, Predoctoral fellow
Irene Mena Palomo, Graduate student
Nuria García Hurtado, Graduate student
Andrea Guajardo Grence, Undergraduate student
Laura Vela Martín, Undergraduate student
Enrique Alfaro García, Undergraduate student
Lorena Barreras Romero, Technician
Track record of the group
During last years our research group is devoted to the analysis of meiotic divisions in male mouse as a model organism. Meiosis is a process of cell division that generates haploid gametes, the spermatozoids and the ovules. Errors in chromosome segregation during meiosis promote spontaneous miscarriages, different forms of infertility, and may promote the appearance of aneuploidies such as the Down syndrome, of high socioeconomic impact.
We have mainly focussed out attention in the study of the recruitment, distribution, dynamics and function of the proteins present at the inner centromere domain, during both meiotic divisions. The proteins at the inner centromere domain maintain sister chromatid cohesion until the anaphase of the second meiotic division, and are also involved in the correction of errors in the attachment of microtubules with the kinetochores, and some of them act as sensors of the interkinetochoric tension. Among these proteins, and for some time, we analyzed the distribution and dynamics of different subunits of the cohesin complex. Thus, and in collaboration with different national and international groups, we studied the distributions of the subunits SMC1α, SMC1β, SMC3, STAG3, RAD21, RAD21L and REC8; as well as those of some proteins regulating the dynamics of cohesin complexes such as Shugoshin 2 (SGO2), NIPBL, MAU2, and Sororin. In addition, we also analyzed the dynamics and the order of recruitment to the centromere of the proteins of the chromosomal passenger complex Aurora-B, INCENP, Survivin and Borealin. We also analyzed the dynamics of the microtubules depolymerizing kinesin MCAK, and that of DNA Topoisomerase IIα, both of them also localized at the inner centromere domain. Taking into account all our results we proposed a model that suggests that during meiosis II, the changes in interkinetochoric tension are involved in sequential changes in the distribution of different proteins at the inner centromere. The redistribution of some of these proteins then allows the proteolytic degradation of cohesin complexes by Separase, and finally, the decatenation of sister centromeres by DNA Topoisomerase IIα during anaphase II (Figure 1).
We also studied the dynamics of some proteins of the outer kinetochore plate (CENP-E and BubR1); telomere proteins that regulate the attachment of telomeres to the nuclear envelope during the prophase of the first meiotic division (TRF1, RAP1, SUN1, the kinase CDK2, and Ringo A); and the recruitment and behaviour of condensin I and SMC5/6 complexes complexes during both meiotic divisions.
Most relevant publications
Mps1 kinase-dependent Sgo2 centromere localisation mediates cohesin protection in mouse oocyte meiosis I. El Yakoubi W, Buffin E, Cladière D, Gryaznova Y, Berenguer I, Touati SA, Gómez R, Suja JA, van Deursen JM, Wassmann K. Nat Commun. 2017 Sep 25;8(1):694. doi: 10.1038/s41467-017-00774-3
Essential role of the Cdk2 activator RingoA in meiotic telomere tethering to the nuclear envelope. Mikolcevic P, Isoda M, Shibuya H, del Barco Barrantes I, Igea A, Suja JA, Shackleton S, Watanabe Y, Nebreda AR. Nat Commun. 2016 Mar 30;7:11084. doi: 10.1038/ncomms11084.
Sororin loads to the synaptonemal complex central region independently of meiotic cohesin complexes. Gómez R, Felipe-Medina N, Ruiz-Torres M, Berenguer I, Viera A, Pérez S, Barbero JL, Llano E, Fukuda T, Alsheimer M, Pendás AM, Losada A, Suja JA. EMBO Rep. 2016 May;17(5):695-707. doi: 10.15252/embr.201541060. Epub 2016 Mar 7.
SKAP, an outer kinetochore protein, is required for mouse germ cell development. Grey C, Espeut J, Ametsitsi R, Kumar R, Luksza M, Brun C, Verlhac MH, Suja JA, de Massy B. Reproduction. 2016 Mar;151(3):239-51. doi: 10.1530/REP-15-0451. Epub 2015 Dec 14.
CEP63 deficiency promotes p53-dependent microcephaly and reveals a role for the centrosome in meiotic recombination. Marjanović M, Sánchez-Huertas C, Terré B, Gómez R, Scheel JF, Pacheco S, Knobel PA, Martínez-Marchal A, Aivio S, Palenzuela L, Wolfrum U, McKinnon PJ, Suja JA, Roig I, Costanzo V, Lüders J, Stracker TH. Nat Commun. 2015 Jul 9;6:7676. doi: 10.1038/ncomms8676.
CDK2 regulates nuclear envelope protein dynamics and telomere attachment in mouse meiotic prophase. Viera A, Alsheimer M, Gómez R, Berenguer I, Ortega S, Symonds CE, Santamaría D, Benavente R, Suja JA. J Cell Sci. 2015 Jan 1;128(1):88-99. doi: 10.1242/jcs.154922. Epub 2014 Nov 6.
Localisation of the SMC loading complex Nipbl/Mau2 during mammalian meiotic prophase I. Visnes T, Giordano F, Kuznetsova A, Suja JA, Lander AD, Calof AL, Ström L. Chromosoma. 2014 Jun;123(3):239-52. doi: 10.1007/s00412-013-0444-7. Epub 2013 Nov 28.
Cohesin removal precedes topoisomerase IIα-dependent decatenation at centromeres in male mammalian meiosis II. Gómez R, Viera A, Berenguer I, Llano E, Pendás AM, Barbero JL, Kikuchi A, Suja JA. Chromosoma. 2014 Mar;123(1-2):129-46. doi: 10.1007/s00412-013-0434-9. Epub 2013 Sep 8.
Figure 1. Model that shows how the tension-dependent redistribution of SGO2 at the inner centromere during prometaphase II allows the cleavage activity of Separase on cohesin complexes (REC8) at the onset of anaphase II, and then the decatenating activity of DNA Topoisomerase IIα in early anaphase II (Gómez et al., 2014).
Aim of the research work
Our current goal is to analyze the involvement of certain post-translational histone modifications in the recruitment of some proteins present at the inner centromere domain during both mouse meiotic divisions. In this regard, we are studying the function of the kinases BUB1 and Haspin in generating the histone modifications H2AT120ph and H3T3ph, respectively, and the participation of these modifications in the recruitment to the inner centromere of SGO2 and the kinase Aurora-B. These studies involve in first place to determine in wild type mice (WT) the recruitment order and dynamics of the kinases BUB1 and Haspin, as well as those of the histone modifications that they induce. Moreover, we are analyzing the distribution of proteins whose dynamics are regulated by these histone modifications. To understand the function of the kinases BUB1 and Haspin we are also using mutant mice with a lack of the enzymatic activity of the kinase BUB1 (Bub1KD/KD), and “in vitro” cultures of seminiferous tubules in which the enzymatic activity of the kinase Haspin has been chemically inhibited by LDN-192960. In addition, we are also analyzing the function of both kinases at the same time by inhibiting the activity of Haspin on “in vitro” cultures of seminiferous tubules from Bub1KD/KD mutant mice.
On the other hand, we are also studying the function of the cohesin regulatory proteins PDS5A and PDS5B on the dynamics of cohesin complexes, and that of some other cohesin regulatory proteins during male mouse meiosis. In this sense, we are employing WT mice, conditional mutants mice for the proteins PDS5A or PDS5B, and double conditional mutants for both proteins.
Research identification links
ORCID – 0000-0002-4266-795X https://orcid.org/0000-0002-4266-795X
Researcher ID – L-4548-2014