Palazzo, Luca (2010) “A DNA Damage Response (DDR) –independent Role for the Ataxia-Telangiectasia Mutated (ATM) Gene Product". [Tesi di dottorato] (Unpublished)

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Item Type:	Tesi di dottorato
Lingua:	English
Title:	“A DNA Damage Response (DDR) –independent Role for the Ataxia-Telangiectasia Mutated (ATM) Gene Product"
Creators:	Creators Email Palazzo, Luca lu.palazzo@studenti.unina.it
Date:	30 November 2010
Number of Pages:	48
Institution:	Università degli Studi di Napoli Federico II
Department:	Biologia e patologia cellullare e molecolare "L. Califano"
Scuola di dottorato:	Medicina molecolare
Dottorato:	Oncologia ed endocrinologia molecolare
Ciclo di dottorato:	23
Coordinatore del Corso di dottorato:	nome email Santoro, Massimo UNSPECIFIED
Tutor:	nome email Grieco, Domenico domenico.grieco@unina.it
Date:	30 November 2010
Number of Pages:	48
Uncontrolled Keywords:	ATM, Mitosis
Settori scientifico-disciplinari del MIUR:	Area 06 - Scienze mediche > MED/04 - Patologia generale
Date Deposited:	13 Dec 2010 15:10
Last Modified:	30 Apr 2014 19:45
URI:	http://www.fedoa.unina.it/id/eprint/8313
DOI:	10.6092/UNINA/FEDOA/8313

Abstract

Ataxia-Telangiectasia (A-T) is a recessive hereditary syndrome characterized by cerebellar degeneration, telangiectasia, precocious aging, immunodeficiency, cancer predisposition and insulin-resistant diabetes. A-T is caused by defects in Ataxia-Telagiectasia Mutated (Atm) gene. Atm encodes a ser/thr kinase (ATM) of the PI3 kinase family that plays a crucial role in the DNA damage response (DDR). Although some A-T features are easily explained by defects in DDR, others, like precocious aging, insulin-resistant diabetes and the recently described whole chromosome instability, are not. We, thus, searched for possible DDR-independent roles of ATM. To this end, we analyzed human cells in which ATM was chemically or genetically downregulated in the absence of any DNA damaging insult. We observed that ATM downregulation induced abnormal mitotic figures. The phenotypes ranged from abnormal mitotic spindles that were displaced from the cell centre, indicating loss of cortical interaction of astral microtubules, to spindles with extra poles that slowly coalesced to form pseudo-bipolar spindles. Often the extra poles lacked the centrosome marker gamma-tubulin. These alterations resembled that of previously described mitotic phenotypes induced by genetic knock-down of the poly(ADP-ribosyl)-polymerase Tankyrase 1 (TNKS1). The mitotic phenotypes have been ascribed to reduced TNKS1-dependent poly(ADP-ribosyl)ation of the Nuclear and Mitotic Apparatus protein 1 (NuMA1). Indeed, we found that ATM down-regulation impaired mitotic poly(ADP-ribosyl)ation of NuMA1. We further observed that ATM physically interacted with TNKS1. ATM activity was required for TNKS1-dependent poly(ADP-ribosyl)ation of NuMa1, perhaps through ATM-dependent phosphorylation of NuMa1, but not for ATM-TNKS1 interaction. Previous observations have shown that TNKS1 controls telomere length by (poly(ADP-ribosyl)ating TRF1 and glucose uptake by regulating insulin-dependent transport into the plasma-membrane of the glucose transporter Glut-4. We propose that the ATM-dependent control of TNKS1 function, independently of DDR, could explain several A-T features and shed light on new therapeutic approaches for the A-T syndrome.

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