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.
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.
Dellaire
Graham
G
The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
Ching
Reagan W
RW
Ahmed
Kashif
K
Jalali
Farid
F
Tse
Kenneth C K
KC
Bristow
Robert G
RG
Bazett-Jones
David P
DP
D064007:Ataxia Telangiectasia Mutated Proteins; D002110:Caffeine / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology*; D022003:Cell Nucleus Structures / Q000201:enzymology / Q000502:physiology* / Q000648:ultrastructure; D064447:Checkpoint Kinase 2; D002843:Chromatin / Q000648:ultrastructure; D004249:DNA Damage; D004260:DNA Repair / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology; D014176:Protein Biosynthesis / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000502:physiology
D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D002110:Caffeine; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases