Haspin is a serine/threonine atypical kinase that phosphorylates histone H3-T3 during metaphase, promoting the recruitment of the chromosomal passenger complex (CPC) at kinetochores. Haspin depletion leads to cell arrest in mitosis and prevents proper chromosome positioning at the metaphase plate. Saccharomyces cerevisiae genome encodes for two haspin paralogues ALK1 and ALK2. We recently showed that these genes are essential to coordinate polarization and cell cycle progression, ensuring the correct positioning of several polarity factors following a transient mitotic delay. The aim of this project is to identify new processes where haspin kinase is involved. The first part of this work shows that Alk1 has a role at the G2/M transition in S. cerevisiae. These findings constitute the first evidence for Alk1-specific functions that are not shared by its paralogue Alk2. Our results indicate that cells lacking ALK1 are sensitive to Latrunculin A and complete nuclear division within the unbudded mother cells. These observations pointed toward a defect in the morphogenesis checkpoint. We also observed that in absence of ALK1 the Cdc28-Y19 phosphorylation signal decreases significantly during a morphogenetic stress. Exploring the underlying mechanism, we found that the decrease in phosphorylation is caused by a misregulation in Mih1 phosphatase activity in absence of Alk1. Therefore in budding yeast Alk1 modulates G2/M cell cycle switch by regulating Mih1 3 activity. The second part of this work is focused on exploring the role of Alk1 and Alk2 in polarisome dispersion. We show that the previously reported role of haspin in polarization relies on its ability to modulate Ras localization. Our observations are indicative for a mitotic role of Ras, which, by regulating Cdc24 redistribution, influences Cdc42 activation at polarized sites. These observations may help to shed light on alterations in cell polarity, which often constitute the molecular mechanism for cancer insurgence.

YEAST HASPIN KINASE REGULATES MITOTIC CELL CYCLE EVENTS: FROM G2/M TRANSITION TO POLARISOME DISPERSION / M. Galli ; scientific tutor: M. Muzi-Falconi. - : . DIPARTIMENTO DI BIOSCIENZE, 2017 Dec 01. ((29. ciclo, Anno Accademico 2016. [10.13130/galli-martina_phd2017-12-01].

YEAST HASPIN KINASE REGULATES MITOTIC CELL CYCLE EVENTS: FROM G2/M TRANSITION TO POLARISOME DISPERSION

M. Galli
2017-12-01

Abstract

Haspin is a serine/threonine atypical kinase that phosphorylates histone H3-T3 during metaphase, promoting the recruitment of the chromosomal passenger complex (CPC) at kinetochores. Haspin depletion leads to cell arrest in mitosis and prevents proper chromosome positioning at the metaphase plate. Saccharomyces cerevisiae genome encodes for two haspin paralogues ALK1 and ALK2. We recently showed that these genes are essential to coordinate polarization and cell cycle progression, ensuring the correct positioning of several polarity factors following a transient mitotic delay. The aim of this project is to identify new processes where haspin kinase is involved. The first part of this work shows that Alk1 has a role at the G2/M transition in S. cerevisiae. These findings constitute the first evidence for Alk1-specific functions that are not shared by its paralogue Alk2. Our results indicate that cells lacking ALK1 are sensitive to Latrunculin A and complete nuclear division within the unbudded mother cells. These observations pointed toward a defect in the morphogenesis checkpoint. We also observed that in absence of ALK1 the Cdc28-Y19 phosphorylation signal decreases significantly during a morphogenetic stress. Exploring the underlying mechanism, we found that the decrease in phosphorylation is caused by a misregulation in Mih1 phosphatase activity in absence of Alk1. Therefore in budding yeast Alk1 modulates G2/M cell cycle switch by regulating Mih1 3 activity. The second part of this work is focused on exploring the role of Alk1 and Alk2 in polarisome dispersion. We show that the previously reported role of haspin in polarization relies on its ability to modulate Ras localization. Our observations are indicative for a mitotic role of Ras, which, by regulating Cdc24 redistribution, influences Cdc42 activation at polarized sites. These observations may help to shed light on alterations in cell polarity, which often constitute the molecular mechanism for cancer insurgence.
MUZI FALCONI, MARCO
Settore BIO/11 - Biologia Molecolare
YEAST HASPIN KINASE REGULATES MITOTIC CELL CYCLE EVENTS: FROM G2/M TRANSITION TO POLARISOME DISPERSION / M. Galli ; scientific tutor: M. Muzi-Falconi. - : . DIPARTIMENTO DI BIOSCIENZE, 2017 Dec 01. ((29. ciclo, Anno Accademico 2016. [10.13130/galli-martina_phd2017-12-01].
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/532121
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