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

Graham Dellaire; Reagan W Ching; Kashif Ahmed; Farid Jalali; Kenneth C K Tse; Robert G Bristow; David P Bazett-Jones

doi:10.1083/jcb.200604009

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

J Cell Biol. 2006 Oct 9;175(1):55-66. doi: 10.1083/jcb.200604009.

Authors

Graham Dellaire¹, Reagan W Ching, Kashif Ahmed, Farid Jalali, Kenneth C K Tse, Robert G Bristow, David P Bazett-Jones

Affiliation

¹ The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Ataxia Telangiectasia Mutated Proteins
Caffeine / pharmacology
Cell Cycle Proteins / metabolism
Cell Cycle Proteins / physiology*
Cell Nucleus Structures / enzymology
Cell Nucleus Structures / physiology*
Cell Nucleus Structures / ultrastructure
Checkpoint Kinase 2
Chromatin / ultrastructure
DNA Damage*
DNA Repair / physiology
DNA-Binding Proteins / metabolism
DNA-Binding Proteins / physiology
Humans
Nuclear Proteins / metabolism
Nuclear Proteins / physiology
Protein Biosynthesis / physiology
Protein Serine-Threonine Kinases / metabolism
Protein Serine-Threonine Kinases / physiology
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism
Tumor Suppressor Proteins / metabolism
Tumor Suppressor Proteins / physiology

Substances

Cell Cycle Proteins
Chromatin
DNA-Binding Proteins
NBN protein, human
Nuclear Proteins
Tumor Suppressor Protein p53
Tumor Suppressor Proteins
Caffeine
Checkpoint Kinase 2
ATM protein, human
ATR protein, human
Ataxia Telangiectasia Mutated Proteins
CHEK2 protein, human
Protein Serine-Threonine Kinases