Promyelocytic leukemia nuclear bodies behave as DNA damage sensors whose response to DNA double-strand breaks is regulated by NBS1 and the kinases ATM, Chk2, and ATR

• Published in: The Journal of cell biology 2006-10, Vol.175 (1), p.55-66
• Main Authors: Dellaire, Graham, Ching, Reagan W, Ahmed, Kashif, Jalali, Farid, Tse, Kenneth C.K, Bristow, Robert G, Bazett-Jones, David P
• Format: Article
• Language: English
• Subjects: Ataxia Telangiectasia Mutated Proteins; Caffeine - pharmacology; Cell cycle; Cell Cycle Proteins - metabolism; Cell Cycle Proteins - physiology; Cell lines; Cell Nucleus Structures - enzymology; Cell Nucleus Structures - physiology; Cell Nucleus Structures - ultrastructure; Cellular biology; Checkpoint Kinase 2; Chromatin; Chromatin - ultrastructure; Deoxyribonucleic acid; DNA; DNA Damage; DNA repair; DNA Repair - physiology; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; Humans; Interphase; Lasers; Leukemia; Microbodies; Nuclear Proteins - metabolism; Nuclear Proteins - physiology; Protein Biosynthesis - physiology; Protein-Serine-Threonine Kinases - metabolism; Protein-Serine-Threonine Kinases - physiology; Sensors; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - metabolism; Tumor Suppressor Proteins - physiology; Tumors
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.200604009

The promyelocytic leukemia (PML) nuclear body (NB) is a dynamic subnuclear compartment that is implicated in tumor suppression, as well as in the transcription, replication, and repair of DNA. PML NB number can change during the cell cycle, increasing in S phase and in response to cellular stress, including DNA damage. Although topological changes in chromatin after DNA damage may affect the integrity of PML NBs, the molecular or structural basis for an increase in PML NB number has not been elucidated. We demonstrate that after DNA double-strand break induction, the increase in PML NB number is based on a biophysical process, as well as ongoing cell cycle progression and DNA repair. PML NBs increase in number by a supramolecular fission mechanism similar to that observed in S-phase cells, and which is delayed or inhibited by the loss of function of NBS1, ATM, Chk2, and ATR kinase. Therefore, an increase in PML NB number is an intrinsic element of the cellular response to DNA damage.