ATM controls proper mitotic spindle structure.

Abstract

The recessive ataxia-telangiectasia (A-T) syndrome is characterized by cerebellar degeneration, immunodeficiency, cancer susceptibility, premature aging, and insulin-resistant diabetes and is caused by loss of function of the ATM kinase, a member of the phosphoinositide 3-kinase-like protein kinases (PIKKs) family. ATM plays a crucial role in the DNA damage response (DDR); however, the complexity of A-T features suggests that ATM may regulate other cellular functions. Here we show that ATM affects proper bipolar mitotic spindle structure independently of DNA damage. In addition, we find that in mitosis ATM forms a complex with the poly(ADP)ribose (PAR) polymerase Tankyrase (TNKS) 1, the spindle pole protein NuMA1, and breast cancer susceptibility protein BRCA1, another crucial DDR player. Our evidence indicates that the complex is required for efficient poly(ADP)ribosylation of NuMA1. We find further that a mutant NuMA1 version, non-phosphorylatable at potential ATM-dependent phosphorylation sites, is poorly PARylated and induces loss of spindle bipolarity. Our findings may help to explain crucial A-T features and provide further mechanistic rationale for TNKS inhibition in cancer therapy.

• Authors: Luca Palazzo, Rosa Della Monica, Roberta Visconti, Vincenzo Costanzo, Domenico Grieco
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 13 Issue 7 Pg. 1091-100 ( 2014) ISSN: 1551-4005 [Electronic] United States
• PMID: 24553124 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Nuclear
• BRCA1 Protein
• Cell Cycle Proteins
• NUMA1 protein, human
• Nuclear Matrix-Associated Proteins
• Poly(ADP-ribose) Polymerases
• Tankyrases
• TNKS protein, human
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins

Topics

• Antigens, Nuclear (metabolism)
• Ataxia Telangiectasia Mutated Proteins (metabolism)
• BRCA1 Protein (metabolism)
• Cell Cycle Proteins
• Cell Line, Tumor
• DNA Damage
• Humans
• Mitosis (physiology)
• Nuclear Matrix-Associated Proteins (metabolism)
• Phosphorylation
• Poly(ADP-ribose) Polymerases (metabolism)
• Spindle Apparatus (physiology)
• Tankyrases (metabolism)