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Cell Cycle

imatge Central Grup Recerca

Scientific Team

Ethel Queralt
Predoctoral researchers
Yolanda Moyano
Patricia Garcia


The Cell Cycle Group, lead by Ethel Queralt, is part of the Cancer Epigenetics and Biology Program in the Bellvitge Biomedical Research Institute (IDIBELL) in order to cover an even bigger number of fields in the research of Cancer.


In this interesting and exciting program, The Cell Cycle Group bases it's research on the study of the yeast Sacharomyces cerevisae, which thanks to it's genetic tools and the huge similarity to the human cells, makes them a perfect tool for the study and understanding of the Cell Cycle.

Research lines

The Cell Cycle

The cell cycle is an ordered series of events happening in eukaryotic cells to grow and divide into two new cells. Basically, cells must complete four major events during the cell cycle: growth (G1 and G2 phases), replicate the DNA (S phase), segregate the chromosome (M phase) and divide (cytokinesis). How eukaryotes, including human, inherit their nuclear genome is a fundamental question in biology. It also has direct clinical implications as chromosome missegregation is a leading cause for miscarriages and birth defects, and is tightly linked to malignant tumour progression. The cell cyle in budding yeast is very similar to the cell cycle in humans and is regulated by the same proteins that are conserved through evolution.


Mitotic exit

Mitosis is an intricately coordinated set of events that ensures the accurate inheritance of genetic information from one cell generation to the next. Entry into mitosis occurs when the Cdk-cyclinB complex reach a peak of kinase activity. In metaphase the chromosomes are condensed, aligned in the metaphase plaque and attached to the mitotic spindle. Proper attachment of the chromosomes will lead to the activation of the anaphase-promoting complex (APC) by its co-activator Cdc20. APC Cdc20 is an ubiquitin ligase that ubiquitilates securin, an inhibitor of the protease separase. Thereby, securin is degraded by the proteasome and separase is activated. Sister chromatid separation at anaphase onset is triggered when the Scc1 subunit of cohesin is cleaved by separase to destroy the cohesin complex. At this time, APC Cdc20 also targets the cyclin Clb2 for degradation promoting the reduction of Cdk activity. However, cyclin destruction by APC Cdc20 is not sufficient to completely remove all Cdk activity in order to exit from mitosis. For this reason, the activation of the mitotic phosphatase Cdc14 becomes essential. Cdc14 phosphatase directly counteracts the Cdk activity by dephosphorylating the Cdk targets. On the other hand, Cdc14 also contributes to the downregulation of the Cdk activity by dephosphorylating a second co-activator of APC, Cdh1, that complete destruction of all mitotic cyclins, and the Cdk inhibitor Sic1.


In metaphase, Cdc14 is kept inactive in the nucleolus by binding to the nucleolar protein Net1 (also called Cfi1). During anaphase, Cdk-dependent phosphorylation of Net1 release active Cdc14. Phosphorylated Net1 shows reduced affinity for Cdc14 and loose its ability to inhibit Cdc14 in vitro. Two different regulatory pathways are essentials for the Cdc14 release from the nucleolus. During early anaphase the FEAR pathway (Cdc f ourteen e arly a naphase r elease) initiates the Cdc14 release and is kept active later in anaphase by a G protein signalling cascade, the mitotic exit network (MEN). A number of proteins including, Cdk, Slk19, Spo12, Fob1 and separase have been implicated in this early anaphase Cdc14 release. Several mutants in the FEAR show a delay in the Cdc14 release from the nucleolus. Nevertheless, an essential role in Cdc14 activation and mitotic exit for separase has been recently described (Queralt et al., 2006) . The FEAR dependent Cdc14 release requires Net1 phosphorylation at Cdk consensus sites. PP2A Cdc55 phosphatase keeps Net1 under-phosphorylated in metaphase (Queralt et al., 2006) . Separase-dependent PP2A Cdc55 downregulation initiates the Cdk-dependent Net1 phosphorylation specifically in anaphase, when mitotic kinase activity starts to decline. The mechanistic basis for separase-dependent PP2A Cdc55 downregulation remains to be elucidated. Later in anaphase, when the Cdk activity is low, the MEN kinases mantain Net1 phosphorylated and Cdc14 release.


Study of cohesin functions in Cornelia de Lange Syndrome


Cornelia de Lange syndrome (CdLS) is a severe disease characterized by growth and mental retardation, craniofacial anomalies and microcephaly. Mutations in five genes that correspond to 5 cohesin-related proteins have been identified in 75% of individuals with clinically diagnosed CdLS: NIPBL, SMC1A, SMC3, RAD21 and HDAC8. Cohesin complex acts as the chromosomal “glue” and is essential for sister chromatids cohesion and their posterior segregation. Cells derived from CdLS patients show only mild and in some cases no obvious defects in sister chromatid cohesion, suggesting that cohesins are also involved in others unknown functions. Recently, numerous observations that suggest that cohesin has an important role in regulating gene expression have been described; however, the mechanistic basis of this function is still very poorly understood. In this project our main objective is to study how the cohesin mutations found in CdLS patients cause the disease phenotypes.


Our hypothesis is that the CdLS phenotypes are due to alterations in the putative cohesin complex role in gene expression. In this project we aim to get new insight into the cohesin roles in non-diving cells. We expect to further confirm the involvement of cohesin complex in gene expression regulation and how its mutations induce human malignancies as CdLS.

Selected papers


Mitotic Exit Function of Polo-like Kinase Cdc5 Is Dependent on Sequential Activation by Cdk1.


Rodriguez-Rodriguez JA, Moyano Y, Játiva S, Queralt E.


Cell Rep. 2016 May 31;15(9):2050-62. doi: 10.1016/j.celrep.2016.04.079.




De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.


Gil-Rodríguez MC, Deardorff MA, Ansari M, Tan CA, Parenti I, Baquero-Montoya C, Ousager LB, Puisac B, Hernández-Marcos M, Teresa-Rodrigo ME, Marcos-Alcalde I, Wesselink JJ, Lusa-Bernal S, Bijlsma EK, Braunholz D, Bueno-Martinez I, Clark D, Cooper NS, Curry CJ, Fisher R, Fryer A, Ganesh J, Gervasini C, Gillessen-Kaesbach G, Guo Y, Hakonarson H, Hopkin RJ, Kaur M, Keating BJ, Kibaek M, Kinning E, Kleefstra T, Kline AD, Kuchinskaya E, Larizza L, Li YR, Liu X, Mariani M, Picker JD, Pié Á, Pozojevic J, Queralt E, Richer J, Roeder E, Sinha A, Scott RH, So J, Wusik KA, Wilson L, Zhang J, Gómez-Puertas P, Casale CH, Ström L, Selicorni A, Ramos FJ, Jackson LG, Krantz ID, Das S, Hennekam RC, Kaiser FJ, FitzPatrick DR, Pié J.


Hum Mutat. 2015 Apr;36(4):454-62. doi: 10.1002/humu.22761. E




Severe ipsilateral musculoskeletal involvement in a Cornelia de Lange patient with a novel NIPBL mutation.


Baquero-Montoya C, Gil-Rodríguez MC, Hernández-Marcos M, Teresa-Rodrigo ME, Vicente-Gabas A, Bernal ML, Casale CH, Bueno-Lozano G, Bueno-Martínez I, Queralt E, Villa O, Hernando-Davalillo C, Armengol L, Gómez-Puertas P, Puisac B, Selicorni A, Ramos FJ, Pié J.


Eur J Med Genet. 2014 Sep;57(9):503-9. doi: 10.1016/j.ejmg.2014.05.006.


Baro B, Rodriguez-Rodriguez JA, Calabria I, Hernáez ML, Gil C, Queralt E. 2013. Dual regulation of the mitotic exit network (MEN) by PP2A-Cdc55 phosphatase.  PLoS Genet 9(12):e1003966


Baquero-Montoya C, Gil-Rodriguez M, Teresa-Rodrigo M, Hernández-Marcos M, Bueno-Lozano G, Bueno-Martínez I, Remeseiro S, Fernández-Hernández R, Bassecourt-Serra M, Rodríguez de Alba M, Queralt E, Losada A, Puisac B, Ramos F, Pie J. 2013. Could a patient with SMC1A duplication be classified as a human cohesinopathy? Clin Genet May 17


Marquina M, Queralt E, Casamayor A, Ariño J. 2012. Lack ofthe Glc7 phosphatase regulatory subunit Ypi1 activates the morphogenetic checkpoint. Int J Biochem Cell Biol. 2012 44(11):1862-71


Calabria I, Baro B, Rodriguez J, Russiñol N and Queralt E. 2012.  Zds1 regulates PP2ACdc55 activity and Cdc14 activation during mitotic exit via its Zds_motif. Journal of Cell Science. March 2012


Pau Pascual-García, Chhabi K. Govind, Ethel Queralt, Bernardo Cuenca-Bon, Ana Llopis, Sebastián Chavez, Alan G. Hinnebusch and Susana Rodríguez-Navarro. 2008. Sus1 is recruited to coding regions and functions during transcription elongation in association with SAGA and TREX2. Genes Dev. 2008 22(20):2811-22

Queralt E* and Uhlmann F*. 2008. Cdk-counteracting phosphatases unlock mitotic exit. Curr. Opin Cell Biol. 2008, Oct 6 (*co-corresponding authors)

Queralt E* and Uhlmann F*. 2008. Zds1 and Zds2 cooperate with separase to release Cdc14 phosphatase from the nucleolus in early anaphase. J. Cell Biology 2008 Sep 8;182(5):873-83 (*co-corresponding authors)

Tóth A, Queralt E, Uhlmann F, Novák B. 2007. Mitotic exit in two dimensions. J Theor Biol. 2007 Oct 7;248(3):560-73.

Juanes MA, Queralt E, Bañó MC, Igual JC. 2007. Rot1 plays an antagonistic role to Clb2 in actin cytoskeleton dynamics throughout the cell cycle. J Cell Sci. 2007 Jul 15;120(Pt 14):2390-401

Queralt E, Lehane C, Novak B, Uhlmann F. 2006. Downregulation of PP2A(Cdc55) phosphatase by separase initiates mitotic exit in budding yeast. Cell. 2006 May 19;125(4):719-32.

Queralt E, Uhlmann F. 2005. More than a separase. Nat Cell Biol. 2005 Oct;7(10):930-2.

Queralt E, et al. 2005. Functional connection between the Clb5 cyclin, the protein kinase C pathway and the Swi4 transcription factor in Saccharomyces cerevisiae. Genetics. 2005 Dec;171(4):1485-98.

Queralt E, et al. 2004. Functional distinction between Cln1p and Cln2p cyclins in the control of the Saccharomyces cerevisiae mitotic cycle. Genetics. 2004 Sep;168(1):129-40.

Queralt E, et al. 2003. Cell cycle activation of the Swi6p transcription factor is linked to nucleocytoplasmic shuttling. Mol Cell Biol. 2003 May;23(9):3126-40.

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Ethel Queralt
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